1
Nerve Agents GA, GB, GD, GF, and VX1

Acute Exposure Guideline Levels

SUMMARY

The nerve agents for which AEGL analyses have been performed include the G-series agents (GA [tabun], GB [sarin], GD [soman], and GF) and nerve agent VX. These agents are all toxic ester derivatives of phosphonic acid containing either a cyanide, fluoride, or sulfur substituent group; they are commonly termed “nerve” agents as a consequence of their anticholin-

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This Document was prepared by the AEGLs Development Team comprising Annetta Watson, Dennis Opresko, and Robert Young (Oak Ridge National Laboratory) and John Hinz and Glenn Leach (Chemical Managers) of the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances. The NAC reviewed and revised the document and the AEGL values as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 1 Nerve Agents GA, GB, GD, GF, and VX1 Acute Exposure Guideline Levels SUMMARY The nerve agents for which AEGL analyses have been performed include the G-series agents (GA [tabun], GB [sarin], GD [soman], and GF) and nerve agent VX. These agents are all toxic ester derivatives of phosphonic acid containing either a cyanide, fluoride, or sulfur substituent group; they are commonly termed “nerve” agents as a consequence of their anticholin- 1   This Document was prepared by the AEGLs Development Team comprising Annetta Watson, Dennis Opresko, and Robert Young (Oak Ridge National Laboratory) and John Hinz and Glenn Leach (Chemical Managers) of the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances. The NAC reviewed and revised the document and the AEGL values as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 esterase properties. These compounds were developed as chemical warfare agents, and one (agent GB, or sarin) was used by terrorists in the 1995 exposure incident that took place in the Tokyo subway system. The chemical names of these five agents are as follow: agent GA, dimethylamidocyanoethylphosphate (CAS Registry No. 77–81–6); agent GB, isopropyl methylphosphonofluoridate (CAS Registry No. 107–44–8); agent GD, pinacolyl methylphosphonofluoridate (CAS Registry No. 96–64–0); agent GF, O-cyclohexylmethyl-fluorophosphonate (CAS Registry No. 329–99–7); and agent VX, O-ethyl-S-(diisopropylaminoethyl) methyl phosphonothiolate (CAS Registry No. 50782–69–9). The G agents are all viscous liquids of varying volatility (vapor density relative to air between 4.86 and 6.33) with faint odors (“faintly fruit,” or “spicy,” odor of camphor). Toxic effects may occur at vapor concentrations below those of odor detection. Agent VX is a amber-colored liquid with a vapor density of 9.2 (air=1) and is considered odorless. As a consequence, agent VX vapor possesses no olfactory warning properties. The vapor pressures and acute toxicity of these agents are sufficiently high for the vapors to be rapidly lethal. Within the G-series, GB is considered a greater vapor hazard than agent GD. Agent GA represents a smaller vapor hazard and is expected to present a relevant contact hazard. The vapor density of agent GF is intermediate between that of agents GA and GD. Agent VX, which has a vapor density (9.2) greater that of any G agent under consideration, was deliberately formulated to possess a low volatility; VX is approximately 2,000 times less volatile than nerve agent GB (DA 1990). As a consequence, agent VX is a persistent, “terrain denial” military compound with the potential to off-gas toxic vapor for days following surface application. Exposure to acutely toxic concentrations of nerve agents can result in excessive bronchial, salivary, ocular, and intestinal secretions and sweating, miosis, bronchospasm, intestinal hypermotility, bradycardia, muscle fasciculations, twitching, weakness, paralysis, loss of consciousness, convulsions, depression of the central respiratory drive, and death. Minimal effects observed at low vapor concentrations include miosis (contraction of the pupils of the eye, with subsequent decrease in pupil area), tightness of the chest, rhinorrhea, and dyspnea (Dunn and Sidell 1989). The results of agent GB vapor exposure studies conducted with human volunteers indicate that the threshold for miosis and other minimal toxic effects falls in the range of 0.05–0.5 mg/m3 for 10–30 minute (min) exposures. The findings are based on the results of low-concentration nerve agent exposures of informed volunteers who were under clinical supervi-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 sion during the periods of exposure as well as for postexposure periods of several months. A concern associated with symptomatic exposures to anticholinesterase compounds such as the nerve agents is the possibility of chronic neurological effects. There is, at present, no evidence indicating that asymptomatic exposures to any of the nerve agents result in chronic neurological disorders. In general, the available epidemiological data indicate that most clinical signs of toxicity resolve within hours to days; severe miosis can require several months after exposure for resolution. However, several studies have shown that subclinical signs may persist for longer periods. Following the chemical terrorist attacks with nerve agent GB (sarin) that occurred in Japan in 1994 and 1995, clinical signs of agent toxicity were no longer apparent in the surviving victims 3 months (mo) after the exposures had occurred; however, several studies conducted on a small number of asymptomatic individuals 6–8 mo after the attack revealed subclinical signs of neurophysiological deficits as measured by event-related and visual evoked potentials, psychomotor performance, and increases in postural sway. Small but measurable changes in single fibre electromyography (SFEMG) of the forearm were detectable between 4 and 15 mo following exposure to a concentration of agent GB that produced minimal clinical signs and symptoms in fully informed human subjects who were under clinical supervision in compliance with Helsinki accords (Baker and Sedgwick 1996). The SFEMG effects were not clinically significant and were not detectable after 15–30 mo. In a separate study of workers who had been occupationally exposed to agent GB (sarin), altered electroencephalograms (EEGs) were recorded 1 year (y) or more after the last exposure had occurred. Spectral analysis of the EEGs indicated significant increases in brain beta activity (12–30 Hz) in the exposed group when compared with nonexposed controls, and sleep EEGs revealed significantly increased rapid eye movement in the exposed workers; however, those observations were not clinically significant. Increases in beta activity were also observed in rhesus monkeys 1 y after being dosed with GB at 5 mg/kg. Slight, but nonsignificant, increases in beta activity, without deleterious effects on cognitive performance, were reported for marmosets injected with GB at 3.0 mg/kg and tested 15 mo later. The significance of subclinical neurological effects for the long-term health of exposed individuals has not been determined. Animal data from vapor and oral exposure studies for the G-series nerve agents and agent VX suggest that agents GB and VX do not induce

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 reproductive or developmental effects in mammals. Oral exposure studies of agent GD in lab animals as well as injection exposure studies of agent GA likewise suggest a lack of reproductive or development effects for these agents. Neither agent GB nor agent VX were found to be genotoxic in a series of microbial and mammalian assays, but agent GA was reported to be weakly mutagenic. There is no evidence indicating that agents GB, GA, or VX are carcinogenic. Derivation of G-Agent AEGL Estimates The base of data for toxicological effects in humans is more complete for agent GB than for any of the other nerve agents under consideration in this analysis. Furthermore, agent GB is the only G agent for which sufficient human data are available to directly derive AEGL-1 and AEGL-2 estimates, and the only G agent for which sufficient laboratory animal data are available for deriving an AEGL-3 value for all five AEGL time periods. AEGL-1 and AEGL-2 Values for G-series Agents The AEGL-1 values for agent GB were derived from a well-conducted study on adult female Sprague-Dawley rats exposed whole-body in a dynamic airflow chamber to a range of GB vapor concentrations (0.01 to 0.48 mg/m3) over three time durations (10 min, 60 min, or 240 min) (total of 283 agent-exposed rats of which 142 were female and 141 were male) (Mioduszewski et al. 2002b). With the inclusion of range-finding experiments and controls (N=130), a total of 423 rats were used in this well-conducted study, which involved highly credible protocols for GB vapor generation and measurement. Analysis of rat pupil diameters assessed pre-and postexposure allowed determination of EC50 values for miosis (defined as a postexposure pupil diameter of 50% or less of the preexposure diameter in 50% of the exposed population). Blood samples collected from tail vein and heart at 60 min and 7 d postexposure indicated no significant change from preexposure baseline in monitored blood RBC-ChE, butyrylcholinesterase (BuChE) or carboxylesterase. No other clinical signs were evident throughout the duration of the study. Gender differences (females more susceptible) were statistically significant at 10 min (p= 0.014) and 240 min (p=0.023), but not at 60 min (p=0.054). This is a

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 well-defined animal end point in a susceptible gender, and it is transient, reversible, and nondisabling. In terms of potential effects on humans, an EC50 for miosis is not considered an adverse effect. This degree of miosis is the first measurable change, by modern and reproducible techniques, in the continuum of response to anticholinesterase compounds. In bright daylight or under bright lighting, a 50% reduction in pupil diameter would result in greater visual acuity among some members of the affected exposed population and no marked reduction in visual acuity for the majority of the affected population. In twilight or dim light conditions, 50% reduction in pupil diameter in some persons would result in reduced visual acuity and less-than-optimal performance of tasks requiring operation of vehicular controls, monitoring or tracking on computer screens, reading of fine text, or shifts in focus between near and far fields. For individuals with central cataracts, the effects would be more pronounced at all illumination levels. During the Tokyo Subway Incident (terrorist release of GB), persons experiencing ≥50% reduction in pupil diameter were able to self-rescue and to render aid to others. Data from GB vapor studies of nonhuman primates (marmosets, 5 h exposures to GB vapor concentrations at 0.05 to 150 µg/m3) (van Helden et al. 2001, 2002) and human volunteers (minimal and reversible effects of miosis, rhinorrhea, headache, etc., after a 20-min exposure to a GB vapor concentration at 0.05 mg/m3) (Harvey 1952; Johns 1952) are considered secondary and supportive. The human data of Harvey (1952) and Johns (1952) indicate that some adult humans exposed to concentrations within the exposure range tested by Mioduszewski et al. (2002b) would experience some discomfort (headache, eye pain, nausea, etc.) in addition to miosis corresponding to ≤50% pupil area decrement but no disability (see definition of AEGL-1 provided in NRC [2001]). Compared to the available human data, the miosis data derived from the study on rats (Mioduszewski et al. 2002b) are considered a more reliable data set because they are based on current and multiple analytical techniques for quantifying exposures and measuring miosis and because they apply an experimental protocol incorporating sufficiently large test and control populations. With the additional knowledge that the EC50 exhibited by rats in the study of Mioduszewski et al. (2002b) is transient and reversible, the determination was made that EC50 for miosis in female (susceptible gender) SD rats is an appropriate end point for estimating AEGL-1 values. Mioduszewski et al. (2002b) is considered the critical study for derivation of AEGL-1 estimates for agent GB.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 The weight-of-evidence analysis indicates reasonable concordance among AEGL-1 estimates derived from the female Sprague-Dawley rat, the marmoset, and the human data sets identified above. Application of the Mioduszewski et al. (2002b) rat miosis data did not significantly change the interim values for AEGL-1 (based on the human experimental data of Harvey [1952] and Johns [1952]) but confirmed that the interim values were representative, protective, and could be retained as final AEGL-1 values. The AEGL-2 values for agent GB were derived from a study in which miosis, dyspnea, photophobia, inhibition of red blood cell cholinesterase (RBC-ChE), and changes in single fibre electromyography (SFEMG) were observed in human volunteers following a 30-min exposure at 0.5 mg/m3 (Baker and Sedgwick 1996). The SFEMG changes noted in the study were not clinically significant and were not detectable after 15–30 mo. Baker and Sedgwick considered SFEMG changes a possible early indicator or precursor of the nondepolarising neuromuscular block associated with intermediate-syndrome paralysis in severe organophosphorous insecticide poisoning cases. They concluded that the electromyographic changes were persistent (>15 mo), but that they were reversible and subclinical. Although not considered debilitating or permanent effects in themselves, SFEMG changes are considered an early indicator of exposures that potentially could result in more significant effects. Selection of this effect as a protective definition of an AEGL-2 level is considered appropriate given the steep dose-response toxicity curve of nerve agents (Aas et al. 1985; Mioduszewski et al. 2000, 2001, 2002a). The concept of added precaution for steep dose-response is consistent with the emergency planning guidance for nerve agents that was developed by the National Center for Environmental Health of the Centers for Disease Control and Prevention (Thacker 1994). Animals exposed to low concentrations of the G agents exhibit the same signs of toxicity as humans, including miosis, salivation, rhinorrhea, dyspnea, and muscle fasciculations. Studies on dogs and rats indicate that exposures to GB at 0.001 mg/m3 for up to 6 h/d are unlikely to produce any signs of toxicity. Because exposure-response data were not available for all of the AEGL-specific exposure durations, temporal extrapolation was used in the development of AEGL values for some of the AEGL-specific time periods. The concentration-exposure time relationship for many systemically acting vapors and gases may be described by Cn×t=k, where the exponent n ranges from 0.8 to 3.5. The temporal extrapolation used here is based on

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 a log-log linear regression of the LC01 lethality of GB in female Sprague-Dawley rats (Mioduszewski et al. 2000, 2001, 2002a) and a log-log linear regression of female SD rat miosis data following GB vapor exposure for durations of 10–240 min (Mioduszewski et al. 2002b). Regression analysis of the LC01 values yields an n value of 1.93 with an r2 of 0.9948, and regression analysis of the miosis data yields an n value of 2.00 with an r2 of 0.4335 (24 data points; see Appendix B). Given that all mammalian toxicity end points observed in the data set for all nerve agents represent different points on the response continuum for anticholinesterase exposure, and that the mechanism of acute mammalian toxicity (cholinesterase inhibition) is the same for all nerve agents, the experimentally derived n=2 from the Mioduszewski et al. (2000, 2001, 2002a,b) rat lethality and miosis data sets is used as the scaling function for all the AEGL derivations rather than a default value. An n of 1.16 (r2=0.6704) was calculated for comparison using other data (human volunteer) and other end points (e.g., GB-induced miosis in humans; see Appendix B). However, because of uncertainties associated with some of the exposure measurements in the earlier studies, the Mioduszewki et al. rat data were determined to be the best source of an estimate for n. The n value of 2 was used to extrapolate for exposure time periods for which there were no experimental data. Those included (1) the 8-h AEGL-3 value (extrapolated from experimental data for 6 h); (2) the 30-min and 8-h AEGL-1 values (extrapolated from 10-min and 4-h experimental data; and (3) all of the AEGL-2 values (extrapolated from experimental data for 30 min). In consultation with experimental investigators at Porton Down (United Kingdom) and the TNO Prins Maurits Laboratory (Netherlands), the analysis has determined that the miotogenic response of mammalian eyes to agent GB vapor exposure is similar across species. The species evaluated include standard laboratory animals (rabbits, rats, guinea pigs), nonhuman primates (marmosets), and humans. As a consequence, the interspecies uncertainty factor (UF) for the critical AEGL-1 end point of miosis is considered equal to 1. To accommodate known variation in human cholinesterase and carboxylesterase activity that may make some individuals susceptible to the effects of cholinesterase inhibitors such as nerve agents, a factor of 10 was applied for intraspecies variability (protection of susceptible populations). A modifying factor is not applicable. Thus, the total UF for estimating AEGL-1 values for agent GB is 10. The fact that AEGL-2 analyses for agent GB are based on data from human volunteers (Baker and Sedgwick 1996) precludes the use of an interspecies UF. As was the case in the AEGL-1 estimations, a factor of 10 was

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 applied for intraspecies variability (protection of susceptible populations). A modifying factor is not applicable. Thus, the total UF for estimating AEGL-2 values for agent GB is 10. In comparison to the data set for agent GB, the data sets characterizing the toxicity of agents GA, GD, and GF are less complete. However, the database for the G agents as a group is considered reasonably complete in that there is/are (1) experimental data for multiple species, including humans; (2) documented nonlethal and lethal end points that follow an exposure-response curve; (3) a known mechanism of toxicity common to all the G agents with all end points representing a response continuum to inhibition of cholinesterase activity; and (4) no uncertainties regarding other toxic end points such as reproductive or developmental effects or carcinogenicity. Because the mechanism of action is the same for all the G agents, data uncertainty is reduced, and target organ effects are expected to be identical, but different in magnitude. Thus, it was possible to develop AEGL estimates for agents GA, GD, and GF by a comparative method of relative potency analysis from the more complete data set for agent GB. This concept has been applied before in the estimation of G-series nerve agent exposure limits, most recently by Mioduszewski et al. (1998). The AEGL-1 and AEGL-2 values for agents GA, GD, and GF were derived from the AEGL-1 and AEGL-2 values for GB using a relative potency approach based on the potency of the agents needed to induce LOAEL effects of miosis, rhinorrhea, and SFEMG and agent concentration in milligrams per cubic meter. Agents GA and GB were considered to have an equivalent potency for causing miosis; thus, the AEGL-1 values for agents GA and GB are equal in milligrams per cubic meter. Agents GD and GF are considered approximately 2 times as potent as agents GB or GA for these end points, and equipotent to each other for AEGL-1 and AEGL-2 effects. Thus, the AEGL-1 and AEGL-2 concentration values for agents GD and GF are equal to 0.5 times those values derived for agents GA and GB, in milligrams per cubic meter. AEGL-3 Values for G-Series Agents AEGL-3 values for agent GB were derived from recent inhalation studies in which the lethality of GB vapor in female Sprague-Dawley rats was evaluated for 10-, 30-, 60-, 90-, 240-, and 360-min time periods (Mioduszewski et al. 2000, 2001, 2002a). Both experimental LC01 and LC50 values were evaluated. The use of a rat data set resulted in selection

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 of an interspecies UF of 3; the full default value of 10 was not considered appropriate because the mechanism of toxicity in rats and humans is the same, and lethality represents one point on the response continuum for these anticholinesterase compounds. The full default value of 10 for intraspecies uncertainty was considered necessary to protect susceptible populations. Because a modifying factor is not applicable, the composite UF for AEGL-3 determination for agent GB is equal to 30. The AEGL-3 values for agent GA were derived from the AEGL-3 values for GB using a relative potency approach based on lethality of the agents; the potency of agent GA was considered to be only one-half that of agent GB for this end point. Thus, the AEGL-3 concentration values for agent GA are equal to 2.0 times the AEGL-3 values for agent GB, in milligrams per cubic meter. The lethal potencies of agents GD and GF are considered equivalent and equipotent to that of agent GB; thus, the AEGL-3 concentration values for agent GB, GD, and GF are equal in milligrams per cubic meter, and the same composite UF (30) was applied in the derivation of the AEGL-3 values for agents GB, GD, and GF. For comparison, AEGL-3 values for GD were alternately derived from a secondary and short-term GD inhalation study of rat lethality for exposure times ≤30 min (Aas et al. 1985). As was the case in the derivation of the GB AEGLs, an n value of 2 was used for extrapolating to different time periods; however, because of the sparse data set for GD, the full default values for interspecies (10) and intraspecies (10) uncertainty were applied to the Aas et al. (1985) data. Because a modifying factor is not applicable, a composite UF of 100 was used for the Aas et al. (1985) data, whereas in the GB AEGL derivation from the Mioduszewski et al. (2000, 2001, 2002a) rat lethality data, a composite UF of 30 was used. The resulting 10-min AEGL-3 (0.27 mg/m3) and 30-min AEGL-3 (0.15 mg/m3) estimates for agent GD from Aas et al. (1985) are very similar to those for GB (0.38 mg/m3 for 10 min and 0.19 mg/m3 for 30 min) from Mioduszewski et al. (2000, 2001, 2002a) and support the assumption of lethal equipotency for agents GB and GD. Derivation of Agent VX AEGL Estimates Insufficient data are available from which to directly derive AEGL values for VX from human or animal inhalation toxicity studies. The few studies available are historical and are considered nonverifiable because of flawed study design, poor sampling techniques, or suspect contamination

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 of sampling and detection apparatus. Nevertheless, available literature clearly indicates that inhibition of cholinesterase activity is a common mechanism of toxicity shared by the G-series nerve agents and nerve agent VX. Thus, it was possible to develop AEGL estimates for agent VX by a comparative method of relative potency analysis from the more complete data set for nerve agent GB. The concept has been applied before in the estimation of agent VX exposure limits, most recently by Reutter et al. (2000). There are a number of estimates in the literature regarding the potency of VX relative to agent GB; all estimates indicate that vapor toxicity for agent VX is greater than that for agent GB. Comparable RBC-ChE50 data from clinically supervised human volunteers (Grob and Harvey 1958; Sidell and Groff 1974), who were exposed to agents GB and VX during well-conducted studies, are available for estimation of relative potency. The human data indicate that agent VX is approximately 4 times more potent than agent GB for inducing the RBC-ChE50 end point, which is considered an early and quantitative measure of the response continuum known for those compounds. Thus, the GB:VX relative potency ratio of 4 is considered an appropriate estimate of GB:VX relative potency for all VX AEGL determinations. All mammalian toxicity end points observed in the data set for nerve agent VX as well as the G-series agents represent different points on the response continuum for anticholinesterase effects. Further, the mechanism of mammalian toxicity (cholinesterase inhibition) is the same for all nerve agents. In consequence, the experimentally derived n=2 from the Mioduszewski et al. (2000, 2001, 2002a,b) rat miosis and lethality data sets for agent GB are used as the scaling function for the agent-VX AEGL-1, AEGL-2, and AEGL-3 derivations rather than a default value. By applying the GB:VX relative potency concept outlined above (the relative potency of GB:VX equal to 4), the AEGL-1 analyses for agent VX are derived from miosis data for adult female SD rats exposed to GB vapor for three time durations of significance for AEGLs (10, 60, and 240 min) (Mioduszewski et al. 2002b). Data from a GB vapor study of nonhuman primates (marmosets, 5 h exposures to GB vapor concentrations at 0.05–150 µg/m3) (van Helden et al. 2001, 2002) and human volunteers (minimal and reversible effects of miosis, rhinorrhea, headache, etc., after a 20-min exposure to a GB vapor concentration at 0.05 mg/m3) (Harvey 1952; Johns 1952) are considered secondary and supportive. The same UFs and logic applied in the derivation of AEGL-1 and AEGL-2 values for agent GB (e.g., interspecies UF of 1, intraspecies UF of 10) are used here for estimat-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 ing AEGL-1 and AEGL-2 values for agent VX. With application of a modifying factor of 3 for the sparse VX data set, the total UF for estimating AEGL-1 values for agent VX (from the GB data set of Mioduszewski et al. [2002b]) is 30. By further application of the GB:VX relative potency concept outlined above, the AEGL-2 values for agent VX were derived from a GB vapor exposure study of human subjects in which miosis, dyspnea, photophobia, inhibition of red blood cell cholinesterase (RBC-ChE) to approximately 60% of individual baseline, and small but measurable changes in SFEMG of the forearm occurred following a 30-min exposure at 0.5 mg GB/m3 (Baker and Sedgwick 1996). The fact that AEGL-2 analyses for agent VX are based on data from clinically supervised human volunteers exposed to GB vapor (Baker and Sedgwick 1996) precludes the use of an interspecies UF. With application of a factor of 10 for intraspecies variability and a modifying factor of 3 for the sparse VX data set, the total UF for estimating AEGL-2 values for agent VX (from the GB data set of Baker and Sedgwick [1996]) is 30. By further application of the GB:VX relative potency concept outlined above, the AEGL-3 values for agent VX were derived from recent inhalation studies in which the lethality of GB to female Sprague-Dawley rats was evaluated for the 10-, 30-, 60-, 90-, 240-, and 360-min time periods (Mioduszewski et al. 2000, 2001, 2002a). Both experimental LC01 and LC50 values were evaluated. The same UFs and logic applied in the derivation of AEGL-3 values for agent GB (interspecies UF of 3 and an intraspecies UF of 10) are used here for agent VX. With the additional application of a modifying factor of 3 for the sparse VX data set, the total UF for AEGL-3 determination for agent VX is equal to 100. Research Needs G-Series Agents Further data analysis and experimentation is needed to more fully understand gender differences in susceptibility to nonlethal and lethal end points among the test population of SD rats. Interspecies susceptibility could be more fully characterized by determining if similar results can be obtained for the same protocol with different test species (particularly nonhuman primates). The scarcity of dose-response data for agents GA, GD, and GF forces

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 usually included as a basis for AEGL-2 estimation. However, due to the known steep dose response for nerve agent vapor exposure, incorporation of the long-lasting SFEMG end point is here considered a protective interpretation of the AEGL-2 definition. The point of departure for AEGL- 2 estimation is 0.5 mg/m3 for 30 min. Uncertainty Factors/Rationale: Based on relative potency estimate from Section 4.3 and Mioduszewski et al. (1998) study showing that agent GF is approximately twice as potent as agents GB and GA for AEGL-2 effects (please see derivation for GB AEGL-2). Total uncertainty factor: 10 Interspecies: 1 (human data). Intraspecies: 10—for susceptible human subpopulations. Some individuals possess abnormally low levels of blood cholinesterase and carboxylesterase activity that may make them especially susceptible to the effects of cholinesterase inhibitors such as nerve agents (see Section 4.5.3). Therefore, a factor of 10 was retained. Modifying factor: None (see derivation for agent GB). Animal to human dosimetric adjustment: None applied (human data). Time scaling: Based on relative potency estimate from Section 4.3 and Mioduszewski et al. (1998)—agent GF is approximately twice as potent as agents GB and GA for AEGL-2 effects (please see derivation for GB AEGL-2) and Cn×t=k where n=2 and k=0.0013 mg/m3×h for agent GB. Data adequacy: Based on relative potency estimate from Section 4.3 and Mioduszewski et al. (1998)—agent GF is approximately twice as potent as agents GB and GA for AEGL-2 effects (please see derivation for GB AEGL-2). The scarcity of dose-response data for agent GF forces the AEGL analysis to rely on assumptions of relative potency. Thus, AEGL values for agent GF are derivative. The relative potency assumptions for estimating AEGL-2 values for agent GF from the available database for agent GB need experimental confirmation.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 AEGL-3 10 min 30 min 1 h 4 h 8 h 0.053 ppm (0.38 mg/m3) 0.027 ppm (0.19 mg/m3) 0.018 ppm (0.13 mg/m3) 0.0098 ppm (0.070 mg/m3) 0.0071 ppm (0.051 mg/m3) Key Reference: (1) Mioduszewski, R.J., Manthei, J., Way, R., Burnett, D., Gaviola, B.Muse, W., Thomson, S., Sommerville, D. and Crosier, R. 2000. Estimating the probability of sarin vapor toxicity in rats as a function of exposure concentration and duration. Proceedings of the International Chemical Weapons Demilitarization Conference (CWD-2000), The Hague, NL. May 21–24, 2000. (2) Mioduszewski, R.J., Manthei, J., Way, R., Burnett, D., Gaviola, B., Muse, W., Anthony, J., Durst, D., Sommerville, D., Crosier, R., Thomson, S, and Crouse, C. 2001. ECBC Low Level Operational Toxicology Program: Phase I—Inhalation toxicity of sarin vapor in rats as a function of exposure concentration and duration. ECBC-TR-183, Edgewood Research Development and Engineering Center, Aberdeen Proving Ground, MD. (August 2001). (3) Mioduszewski, R.J., Manthei, J., Way, R., Burnett, D., Gaviola, B.Muse, W., Thomson, S., Sommerville, D., and Crosier, R. 2002a. Interaction of exposure concentration and duration in determining acute toxic effects of sarin vapor in rats. Toxicol. Sci. 66:176–184. Secondary reference: Anthony, J.S., Haley, M.V., Manthei, J.H., Way, R.A., Burnett, D.C., Gaviola, B.P., Sommerville, D.R., Crosier, R.B., Mioduszewski, R.J., Jakubouwski, E.M., Montgomery, J.L., Thomson, S.A. 2002. Inhalation toxicity of GF vapor in rats as a function of exposure concentration and duration and its potency comparison to GB. Late-breaking Poster presented at 41st Annual meeting of the Society of Toxicology, Nashville, TN (21 Mar 2002). Test species/strain/gender/number: Based on relative potency estimate from Section 4.3 of this document and Mioduszewski et al. (1998)—agent GF is equipotent to agent GB for lethality (please see derivation for GB AEGL-3 derived from female Sprague-Dawley rat data). This assumption is supported by the recent study of Anthony et al. (2002). Exposure route/concentrations/durations: Based on relative potency estimate from Section 4.3, Mioduszewski et al. (1998), and Anthony et al. (2002)—

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 agent GF is equipotent to agent GB for lethality (please see derivation for GB AEGL-3) and study of rat inhalation toxicity in dynamic mode exposure chamber (Mioduszewski et al. 2000, 2001, 2002a). Effects: Derivation of AEGL-3 values based on relative potency estimate from Section 4.3 and the Mioduszewski et al. (1998) and Anthony et al (2002) studies showing that agent GF is equipotent to agent GB for lethality (please see derivation for GB AEGL-3) and from GB vapor exposure study (Mioduszewski, et al. 2000, 2001, 2002a) in which lethality and sublethal clinical signs monitored during and after exposure. Only lethality data reported at this time. End point/concentration/rationale: Derivation of AEGL-3 values based on relative potency estimate from Section 4.3 and the Mioduszewski et al. (1998) and Anthony et al. (2002) studies showing that agent GF is equipotent to agent GB for lethality (please see derivation for GB AEGL-3) and from GB vapor exposure study (Mioduszewski et al. 2000, 2001, 2002a) which derived 14-d lethality estimates for female Sprague-Dawley rats (female rats were reported to be overall more sensitive to GB vapor toxicity than male rats over the range of exposure concentrations and durations studied). Gender differences in sensitivity are reported to be statistically significant at p<0.01 (Mioduszewski et al. 2000, 2001, 2002a). End point concentrations for LC01 reported for female SD rats (the susceptible gender) are used as points of departure from which to derive AEGL-3 estimates. Probit analysis (MINITAB, version 13) presented in the Mioduszewski et al. (2000) study provided 14-d LC50 and LC01 values for female rats. Uncertainty factors/rationale: Based on relative potency estimate from Section 4.3 and the Mioduszewski et al. (1998), and Anthony et al. (2002) studies showing that agent GF is equipotent to agent GB for lethality (please see derivation for GB AEGL-3). Total uncertainty factor: 30 Interspecies: 3 (female rat data). The full default value of 10 was not considered necessary because the mechanism of toxicity in both rats and humans is the same, cholinesterase inhibition. Intraspecies: 10—for possible susceptible human individuals. Some individuals possess abnormally low levels of blood cholinesterase and carboxylesterase activity that may make them especially susceptible to the effects of cholinesterase inhibitors such as nerve agents (see Section 4.5.3.). Therefore, a factor of 10 was retained. Modifying factor: None (see derivation for agent GB). Time scaling: Based on relative potency estimate from Section 4.3 of this document, Mioduszewski et al. (1998), and Anthony et al. (2002)—agent GF

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 is equipotent to agent GB for lethality (please see derivation for GB AEGL-3) and Cn×t=k where n=2 and k=0.021 mg/m3×h to extrapolate from 6-h value to 8-h estimate of LC01. Data adequacy: Based on relative potency estimate from Section 4.3, Mioduszewski et al. (1998), and Anthony et al. (2002)—agent GF is equipotent to agent GB for lethality (please see derivation for GB AEGL-3). The scarcity of dose-response data for agent GF forces the AEGL analysis to rely on assumptions of relative potency. Thus, AEGL-3 values for agent GF are derivative. The relative potency assumptions for estimating AEGL-3 values for agent GF from the available database for agent GB need experimental confirmation.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 Derivation Summary for Agent VX Vapor (CAS No. 50782–69–9) (O-Ethyl-S-(Isopropyl-Aminoethyl)Methyl Phosphonothiolate) AEGL-1 10 min 30 min 1 h 4 h 8 h 0.000052 ppm (0.00057 mg/m3) 0.000030 ppm (0.00033 mg/m3) 0.000016 ppm (0.00017 mg/m3) 0.0000091 ppm (0.00010 mg/m3) 0.0000065 ppm (0.000071 mg/m3) Key reference: Mioduszewski et al. (2002b). Low-level sarin vapor exposure in rats: Effect of exposure concentration and duration on pupil size (ECBC-TR-235). Edgewood Chemical Biological Center, U.S. Army Soldier and Biological Chemical Command, Aberdeen Proving Ground, MD. Secondary references: (1) Grob, D., and Harvey, J.C. 1958. Effects in man of the anticholinesterase compound Sarin (isopropyl methyl phosphonofluoridate). J. Clin. Invest. 37:350–368 (2) Sidell, F.R., and Groff, W.A. 1974. The reactivatibility of cholinesterase inhibited by VX and sarin in man. Toxicol. Appl. Pharmacol. 27:241–252. Test species/strain/gender/number: Based on relative potency from Grob and Harvey (1958) and Sidell and Groff (1974)—potency of agent VX is approximately 4 times that of agent GB for AEGL-1 effects (please see derivation for GB AEGL-1, derived from female Sprague-Dawley rat data for EC50 miosis). Exposure route/concentrations/durations: Based on relative potency from Grob and Harvey (1958) and Sidell and Groff (1974)—potency of agent VX is approximately 4 times that of agent GB for AEGL-1 effects (please see derivation for GB AEGL-1) and derived from GB vapor exposures to female Sprague-Dawley rats for EC50 miosis at 10, 60, and 240 min Effects: Derivation of AEGL-1 values based on relative potency from Grob and Harvey (1958) and Sidell and Groff (1974) studies showing that potency of agent VX is approximately 4 times that of agent GB for AEGL-1 effects (please see derivation for GB AEGL-1) and VX estimates derived from data in GB vapor exposure study (Miodiszewski et al. 2002b) in which EC50 for miosis (a postexposure pupil diameter 50% or less of the preexposure pupil diameter in 50% of the exposed rat population) in female SD rats was determined for 10, 60, and 240 min. Estimated concentrations of VX

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 expected to produce similar effects are 0.017 mg/m3 for 10 min, 0.005 mg/m3 for 60 min, and 0.003 mg/m3 for 240 min. End point/concentration/rationale: Derivation of AEGL-1 values based on relative potency from Grob and Harvey (1958) and Sidell and Groff (1974) studies showing that potency of agent VX is approximately 4 times that of agent GB (please see derivation for GB AEGL-1) and determination that the EC50 for miosis is based on a well-defined animal end point in a susceptible gender and is reversible, local, nondisabling, and transient (Mioduszewski et al. [2002b] study of young female SD rats exposed to GB). Estimated concentrations of VX expected to produce similar effects are 0.017 mg/m3 for 10 min, 0.005 mg/m3 for 60 min, and 0.003 mg/m3 for 240 min; selection of these estimated EC50 concentrations for female SD rats (the susceptible gender) as the points of departure for agent VX AEGL-1 estimation is thus protective. The miosis effects data of van Helden et al. (2001, 2002) (nonhuman primates), Harvey (1952) (human volunteers), and Johns (1952) (human volunteers) are supportive. The EC50 for miosis (a postexposure pupil diameter 50% or less of the preexposure pupil diameter in 50% of the exposed rat population) (Mioduszewski et al. 2002b) is not considered an adverse effect for humans. The AEGL values are estimates for VX vapor exposures only. Uncertainty factors/rationale: Based on relative potency from Grob and Harvey (1958) and Sidell and Groff (1974) studies showing that potency of agent VX is approximately 4 times that of agent GB (please see derivation for GB AEGL-1). Total uncertainty factor: 30 Interspecies: 1—miosis response to nerve agent vapor exposure is similar across mammalian species (as for agent GB AEGL-1 estima tion). Intraspecies: 10—for possible susceptible human individuals. Some individuals possess abnormally low levels of blood cholinesterase activity that may make them especially susceptible to the effects of cholinesterase inhibitors such as nerve agents (Morgan 1989; Wills 1972; Opresko et al. 1998). Therefore, a factor of 10 was retained. Modifying factor: 3 (for sparse VX database). Animal to human dosimetric adjustment: None applied (human data). Time scaling: Based on relative potency from Grob and Harvey (1958) and Sidell and Groff (1974)—potency of agent VX is approximately 4 times that of agent GB (please see derivation for GB AEGL-1) and Cn×t=k where n= 2, and k=5.0×10−8 mg/m3×h for 10 to 30 min extrapolation, and k=4.0× 10−8 mg/m3×h for 4-h to 8-h extrapolation.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 Data adequacy: Based on relative potency—potency of agent VX is approximately 4 times that of agent GB (please see derivation for GB AEGL-1). The scarcity of dose-response data for agent VX forces the AEGL analysis to rely on assumptions of relative potency. Thus, AEGL values for agent VX are derivative. The relative potency assumptions for estimating AEGL-1 values for agent VX from the available database for agent GB need experimental confirmation.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 AEGL-2 10 min 30 min 1 h 4 h 8 h 0.00065 ppm (0.0072 mg/m3) 0.00038 ppm (0.0042 mg/m3) 0.00027 ppm (0.0029 mg/m3) 0.00014 ppm (0.0015 mg/m3) 0.000095 ppm (0.0010 mg/m3) Key reference: Baker, D.J. and Sedgwick, E.M., 1996. Single-fibre electromyographic changes in man after organophosphate exposure. Hum. Exp. Toxicol. 15:369–375. Secondary references: Grob, D., and Harvey, J.C. 1958. Effects in man of the anticholinesterase compound Sarin (isopropyl methyl phosphonofluoridate). J. Clin. Invest. 37:350–368; Sidell, F.R., and Groff, W.A. 1974. The reactivatibility of cholinesterase inhibited by VX and sarin in man. Toxicol. Appl. Pharmacol. 27:241–252. Test species/strain/gender/number: Based on relative potency from Grob and Harvey (1958) and Sidell and Groff (1974)—potency of agent VX is approximately 4 times that of agent GB for AEGL-2 effects (please see derivation for GB AEGL-2 derived from human volunteer data). Exposure route/concentrations/durations: Based on relative potency from Grob and Harvey (1958) and Sidell and Groff (1974)—potency of agent VX is approximately 4 times that of agent GB (please see derivation for GB AEGL-2) and derived from GB vapor inhalation to humans in exposure chamber; 0.5 mg/m3 for 30 min while walking at a rate of 96 paces per minute and breathing normally (Baker and Sedgwick 1996). Effects: Derivation of AEGL-2 values based on relative potency from Grob and Harvey (1958) and Sidell and Groff (1974) studies showing that potency of agent VX is approximately 4 times that of agent GB for AEGL-2 effects (please see derivation for GB AEGL-2). VX estimates derived from GB vapor exposure study (Baker and Sedgwick 1996) in which observed effects included miosis in eight of eight subjects, dyspnea and photophobia in some individuals, inhibition of RBC-ChE to approximately 60% of individual baseline at 3 h and 3 d postexposure in eight of eight subjects, and small but measurable changes in single fibre electromyography (SFEMG) of the forearm that were detectable in the lab between 4 and 15 mo postexposure (but not detectable at 15–30 mo postexposure) in five of eight human volunteers exposed to GB at 0.5 mg/m3 for 30 min. SFEMG changes considered subclinical. No permanent effects. End point/concentration/rationale: Derivation of AEGL-2 values based on relative potency from Grob and Harvey (1958) and Sidell and Groff (1974)

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 studies showing that potency of agent VX is approximately 4 times that of agent GB for AEGL-2 effects (please see derivation for GB AEGL-2) and determination that a 30-min exposure to GB at 0.5 mg/m3 results in a greater level of effect than the EC50 considered for AEGL-1 determination (see Baker and Sedgwick [1996]); thus, there exists a heightened potential for reduced visual acuity following experimental exposures. Estimated concentration of VX expected to produce similar effects is 0.125 mg/m3 for 30 min; this concentration is the point of departure for agent VX AEGL- 2 estimations. Inclusion of the long-lasting but subclinical and fully reversible SFEMG effect is here considered a protective interpretation of the AEGL-2 definition, given the known steep dose response for nerve agent vapor exposure. The AEGL values are estimates for VX vapor exposures only. Uncertainty Factors/Rationale: Based on relative potency from Grob and Harvey (1958) and Sidell and Groff (1974) studies showing that potency of agent VX is approximately 4 times that of agent GB for AEGL-2 effects (please see derivation for GB AEGL-2). Total uncertainty factor: 30 Interspecies: 1 (human data). Intraspecies: 10—for possible susceptible human individuals. Some individuals possess abnormally low levels of blood cholinesterase activity that may make them especially susceptible to the effects of cholinesterase inhibitors such as nerve agents (Morgan 1989; Wills 1972; Opresko et al., 1998). Therefore, a factor of 10 was retained. Modifying factor: 3 (for sparse VX database). Animal to human dosimetric adjustment: None applied (human data) Time scaling: Based on relative potency from Grob and Harvey (1958) and Sidell and Groff (1974)—potency of agent VX is approximately 4 times that of agent GB for AEGL-2 effects (please see derivation for GB AEGL-2) and Cn×t=k where n=2 and k=8.6×10−6 mg/m3×h. Data adequacy: Based on relative potency estimate from Grob and Harvey (1958) and Sidell and Groff (1974)—potency of agent VX is approximately 4 times that of agent GB for AEGL-2 effects (please see derivation for GB AEGL-2). The scarcity of dose-response data for agent VX forces the AEGL analysis to rely on assumptions of relative potency. Thus, AEGL values for agent VX are derivative. The relative potency assumptions for estimating AEGL-2 values for agent VX from the available database for agent GB need experimental confirmation.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 AEGL-3 10 min 30 min 1 h 4 h 8 h 0.0027 ppm (0.029 mg/m3) 0.0014 ppm (0.015 mg/m3) 0.00091 ppm (0.010 mg/m3) 0.00048 ppm (0.0052 mg/m3) 0.00035 ppm (0.0038 mg/m3) Key reference: Mioduszewski et al. 2002a. Interaction of exposure concentration and duration in determining acute toxic effects of sarin vapor in rats. Toxicol. Sci. 66:176–184. Secondary references: (1) Grob, D., and Harvey, J.C. 1958. Effects in man of the anticholinesterase compound Sarin (isopropyl methyl phosphonofluoridate). J. Clin. Invest. 37:350–368. (2) Sidell, F.R., and Groff, W.A. 1974. The reactivatibility of cholinesterase inhibited by VX and sarin in man. Toxicol. Appl. Pharmacol. 27:241–252. Test species/strain/gender/number: Based on assumptions previously stated from Grob and Harvey (1958) and Sidell and Groff (1974)—potency of agent VX is approximately 4 times that of agent GB (please see derivation for GB AEGL-3 derived from female Sprague-Dawley rat data) and RBC-ChE50 is part of an anticholinesterase response continuum. Exposure route/concentrations/durations: Based on assumption previously stated from Grob and Harvey (1958) and Sidell and Groff (1974)—that the potency of agent VX is approximately 4 times that of agent GB (please see derivation for GB AEGL-3) and the study of rat inhalation toxicity in dynamic mode exposure chamber (Mioduszewski et al. 2000, 2001, 2002a). Effects: Derivation of AEGL-3 values based on assumption previously stated from Grob and Harvey (1958) and Sidell and Groff (1974) studies showing that potency of agent VX is approximately 4 times that of agent GB (please see derivation for GB AEGL-3) and from GB vapor exposure study (Mioduszewski et al. 2000, 2001, 2002a) in which lethality and sublethal clinical signs were monitored during and after exposure. Only lethality data reported at this time. End point/concentration/rationale: Derivation of AEGL-3 values based on assumption previously stated from Grob and Harvey (1958) and Sidell and Groff (1974) studies showing that potency of agent VX is approximately 4 times that of agent GB (please see derivation for GB AEGL-3) and from GB vapor exposure study (Mioduszewski et al. 2000, 2001, 2002a) of female SD rats exposed to GB vapor. Gender differences for lethality are significant. The LC01 values for GB exposure were multiplied by a factor of 0.25 to estimate the LC01 value for agent VX. These estimated concentrations for VX

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 LC01 in female SD rats (the susceptible gender) are the points of departure for agent VX AEGL-3 estimations, which are thus protective. The AEGL values are estimates for VX vapor exposures only. Uncertainty factors/rationale: Based on assumption previously stated from Grob and Harvey (1958) and Sidell and Groff (1974) studies showing that potency of agent VX is approximately 4 times that of agent GB (please see derivation for GB AEGL-3). Total uncertainty factor: 100 Interspecies: 3—female rat data. The full default value of 10 is not considered appropriate because the mechanism of toxicity in lab rodents and humans is ChE inhibition. Intraspecies: 10—for possible susceptible human individuals. Some individuals possess abnormally low levels of blood cholinesterase and carboxylesterase activity that may make them especially susceptible to the effects of cholinesterase inhibitors such as nerve agents (Morgan 1989; Wills 1972; Opresko et al. 1998). Therefore, a factor of 10 was retained. Modifying factor: 3 (for sparse VX database). Animal to human dosimetric adjustment: None applied (insufficient data) Time scaling: Cn×t=k where n=2 and k=1.16×10−4 mg/m3×h, based on the assumption that the scaling function for agent VX is similar to that derived for agent GB from the experimental rat data of Mioduszewski et al. (2000, 2001, 2002a,b). Extrapolation from 6-h experimental value to 8-h AEGL-3. Data adequacy: The scarcity of dose-response data for agent VX forces the AEGL analysis to rely on assumptions of relative potency. Thus, AEGL values for agent VX are derivative. The relative potency assumptions for estimating AEGL-3 values for agent VX from the available database for agent GB need experimental confirmation.