Appendix C
Health Risk Assessment for The Nerve Agent GD (Soman)



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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Appendix C Health Risk Assessment for The Nerve Agent GD (Soman)

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents This page in the original is blank.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents HEALTH RISK ASSESSMENT FOR NERVE AGENT GD (SOMAN) DRAFT REPORT September 1996 (editorial corrections made April 1997) Prepared for Environmental Risk Assessment Program Strategic Environmental Research Development Program Prepared by Life Sciences Division OAK RIDGE NATIONAL LABORATORY* Oak Ridge, Tennessee 37831 Submitted to Material Chemical Working Group Advisory and Coordinating Committee Environmental Risk Assessment Program Strategic Environmental Research Development Program *   Managed by Lockheed Martin Energy Research Corp. for the U.S. Department of Energy under Contract No. DE-AC05-96OR22464

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents DISCLAIMER This document is an internal review draft for review purposes only and does not constitute U.S. Government policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents PREFACE This report assesses the potential non-cancer and cancer effects of chemical agent GD (CAS No. 96-64-0). This document supports the activities of the Material/Chemical Risk Assessment Working Group of the Environmental Risk Assessment Program, a cooperative endeavor of the Department of Defense, Department of Energy, and Environmental Protection Agency. This working group is developing toxicity values for selected chemicals of concern at federal facilities. Toxicity values will be submitted for consideration by the EPA's IRIS Consensus Process for inclusion on IRIS (EPA's Integrated Risk Information System). The Material/Chemical Risk Assessment Working Group consists of Drs. Jim Cogliano (chair) and Harlal Choudhury (U.S. EPA), Dr. Bruce Briggs (Geo-Centers); Lt. Cmdr. Warren Jederberg and Dr. Robert L. Carpenter (U.S. Naval Medical Research Institute); Dr. Elizabeth Maull and Mr. John Hinz (U.S. Air Force Occupational and Environmental Health Directorate); Drs. Glenn Leach and Winnie Palmer (U.S. Army Center for Health Promotion and Preventive Medicine); Drs. Robert Young and Po-Yung Lu (Oak Ridge National Laboratory). This document was written by Dr. Robert A. Young, Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, TN. Internal peer review was provided by Dr. Robert Young, Dr. Annetta Watson, and Mr. Robert Ross.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents TABLE OF CONTENTS     1. Introduction   1     1.1 Physical/Chemical Properties   1     1.2 Environmental Fate   1     1.2.1 Air   1     1.2.2 Water   1     1.2.3 Soil   1     2. Mechanism of Action   2     2.1 Effects of Organophosphate Agents on the Nervous System   2     2.2 Effect on Blood Cholinesterases   3     2.2.1 Intra- and Interspecies Variation in Blood Cholinesterase Activity   4     2.2.2 Potency of Nerve Agents as Cholinesterase Inhibitors   4     3. Toxicology   5     3.1 Introduction   5     3.2 Short-term Toxicity   6     3.3 Subchronic Toxicity   7     3.4 Chronic Toxicity   12     3.5 Nervous System Toxicity   12     3.6 Developmental and Reproductive Effects   12     3.7 Carcinogenicity and Genotoxicity   12     4. Oral Reference Dose for GD   13     4.1 Cholinesterase Inhibition as an RfD Endpoint   13     4.2 Derivation of RfD   14     4.3 Comparison of RfD with Toxicity Data   15     5. Carcinogenicity Assessment for GD   16     6. References Cited   17     Appendix A   A-1 LIST OF TABLES Table 1.   RBC-ChE Activity in Different Species   5 Table 2.   Lethality Data for Agent GD   7 Table 3.   RBC-ChE Levels in 90-Day Subchronic Study of GD   8 Table 4.   Plasma-ChE Levels in 90-Day Subchronic Study of GD   9 Table 5.   GD-Induced RBC-AChE Inhibition in Female Rats   10 Table 6.   GD-Induced RBC-AChE Inhibition in Male Rats   10 Table 7.   GD-Induced Plasma-AChE Inhibition in Female Rats   11 Table 8.   GD-Induced Plasma-AChE Inhibition in Male Rats   11

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 1. INTRODUCTION Military nerve agents are organophosphate compounds containing either a fluorine, sulfur, or cyanide substituent group (Dacre, 1984). GD contains a fluoride substituent group (GA contains a cyanide substituent group and VX a sulfur group). The chemical synonyms, Chemical Abstract Service (CAS) and Army identification numbers (DA, 1974; Dacre, 1984), and chemical formula for GD are as follows: Agent GD: Methylphosphonofluoridic acid, 1,2,2-trimethylpropyl ester; Pinacoloxymethylphosphoryl fluoride; Pinacolyl methylphosphonofluorididate; Soman CAS No. 96-64-0; 1.1 PHYSICAL/CHEMICAL PROPERTIES Agent GD is a colorless liquid with a molecular weight of 182.2 (DA, 1974); it has a vapor density of 6.3 (air = 1) and a liquid density of 1.02 g/mL at 25°C (DA, 1974). The vapor pressure of GD is 0.4 mm Hg at 25°C. In distilled water it has a solubility of 21 g/L at 20°C (DA, 1974). 1.2 ENVIRONMENTAL FATE 1.2.1 Air Data specifically regarding the fate of GD in the atmosphere were not located. However, because of its volatility, GD is expected to disperse realtively quickly. 1.2.2 Water Agent GD may hydrolyze to relatively nontoxic hydroflouric and pinacolyl methylphosphonic acids (MacNaughton and Brewer, 1994; Rosenblatt et al., 1995). The hydrolysis rate is a function of temperature and pH; the rate is minimum between pH 4 and 6. The t1/2 for GD is approximately 100 hours with 20 × t1/2 being required to attain a 1 × 106 reduction in GD concentration. 1.2.3 Soil GD is likely to undergo hydrolysis in most soils. As noted above, the rate of hydrolysis will be dependent upon temperature and pH. According to Morrill et al. (1985), evaporation is the primary mechanism for the loss of the GA and GB nerve agents from soil. Although the G agents are liquids under ordinary environmental conditions, their relatively high volatility and vapor pressure permits them to be disseminated in vapor form. Because of this volatility, GD is not expected to persist in soils.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 2. MECHANISM OF ACTION Nerve agents are inhibitors of acetylcholinesterase (AChE), an enzyme responsible for deactivating the neurotransmitter acetylcholine (AChE) at some neuronal synapses and myoneural junctions. By a mechanism of phosphorylation, nerve agents act as substrates for the enzyme thereby preventing deactivation of acetylcholine. The organophosphate-inhibited enzyme can be reactivated by dephosphorylation, but this occurs at a rate that is slower than the rate of reactivation of acetylcholine (deactivated by acetylcholinesterase). Consequently, there is a depletion of acetylcholinesterase and a buildup of acetylcholine. In addition, the nerve agent-enzyme complex can also undergo an ''aging" process (thought to be due to a loss of an alkyl or alkoxy group), whereby it becomes resistant to dephosphorylation (see review by Munro et al., 1994). Differences in rates of aging and reactivation may be important in evaluating toxicity data especially when extrapolating from animal studies to humans. In vitro tests conducted by Grob and Harvey (1958) indicate that both GA and GB combine with cholinesterase almost irreversibly during the first hour of their reaction. Sidell and Groff (1974) reported that the GB-ChE complex ages very rapidly in vivo, with 45–70% completion by 5 hours after infusion. In contrast, the complex formed between ChE and the nerve agent VX does not age significantly, and the rate of spontaneous reactivation can be as fast as 1%/hr in humans (Sidell and Groff, 1974). 2.1 Effects of Organophosphate Agents on the Nervous System The anticholinesterase effects of the organophosphate nerve agents can be characterized as being muscarinic, nicotinic, or central nervous system (CNS)-related. Muscarinic effects occur in the parasympathetic system (bronchi, heart, pupils of the eyes; and salivary, lacrimal and sweat glands) and result in signs of pulmonary edema, bradycardia, miosis, tearing, and sweating. Nicotinic effects occur in somatic (skeletal/motor) and sympathetic systems, and result in muscle fasciculation, muscle weakness, tachycardia, and diarrhea. Effects on the CNS by organophosphates are manifested as giddiness, anxiety, emotional lability, ataxia, confusion, and depression (O'Brien, 1960). Although the inhibition of cholinesterase within neuro-effector junctions or the effector itself is thought to be responsible for the major toxic effects of organophosphate agents, these compounds can apparently affect nerve-impulse transmission by more direct processes as well. Direct effects may occur on excitable tissues, receptors, and ionic channels. According to Somani et al. (1992), the direct action of nerve agents on nicotinic and muscarinic ACh receptors may occur when concentrations in the blood rise above micromolar levels, whereas at lower levels the action is mainly the result of inhibition of AChE. Albuquerque et al. (1985) have shown that agent GA, as well as agents GB and GD are capable of changing receptor sites in a manner similar to that exhibited by acetylcholine, which promotes the conductance of electrophysiological signals associated with stimulation of neuromuscular function. VX "may directly affect a small population of muscarinic ACh receptors that have a high affinity for [3H]-cis-methyldioxalane binding" (Somani et al., 1992). VX may also counteract the effects of ACh by acting as an open channel blocker at the neuromuscular junction, thereby interrupting neuromuscular function (Rickett et al., 1987). Exposure to some organophosphate cholinesterase inhibitors results in a delayed neuropathy characterized by degeneration of axons and myelin. This effect is not associated with the inhibition of acetylcholinesterase, but rather with the inhibition of an enzyme described as neuropathy target esterase (NTE); however, the exact mechanism of toxicity is not yet fully understood (Munro et al., 1994). For some organophosphate compounds, delayed neuropathy can be induced in experimental animals at relatively low exposure levels, whereas for others the effect is only seen following exposure to supralethal doses when the animal is protected from the acute toxic effects caused by cholinesterase inhibition.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Although there is the potential for nerve agents to have direct toxic effects on the nervous system or to cause delayed neuropathy, there is no evidence that such effects occur in humans at doses lower than those causing cholinesterase inhibition. However, it should be noted that there is very little animal or human data evaluating the potential effects of long-term exposure to low doses. Nevertheless, for the purpose of evaluating potential health effects, inhibition of cholinesterase is generally considered the most useful biological endpoint. 2.2 Effect on Blood Cholinesterases In addition to being found in the nervous system, acetylcholinesterase also occurs in the blood where it is bound to the surface of red blood cells (termed RBC-ChE or RBC-AChE). RBC-AChE activity, as well as the activity of a second type of cholinesterase found in blood plasma (butyrylcholinesterase, or plasma cholinesterase) have been used to monitor exposure to organophosphate compounds (pesticides and nerve agents). Because ACh is the primary neurotransmitter of the nervous system, changes in RBC-AChE activity are generally considered to be the more appropriate bioindicators of potential effects (Morgan, 1989). There is also evidence that RBC-AChE is as sensitive as brain ChE to the effects of nerve agents. Grob and Harvey (1958) reported that the in vitro concentrations producing 50% depression of brain-ChE and RBC-AChE activity were the same in the case of GA (1.5 × 10-8 mol/L), and only slightly different (3 × 10-9 mol/L and 3.3 × 10-9 mol/L) in the case of GB. However, in vivo animal studies indicate a poor correlation between brain and RBC-AChE in cases of acute exposures (Jimmerson et al., 1989), and this is reflected in the fact that blood cholinesterase activity may not always be correlated with exposure or with signs and symptoms of toxicity (Holmstedt, 1959). Acute exposures to high concentrations may cause immediate toxic effects before significant changes occur in blood ChE activity, and repeated exposures over a period of several days or more may result in a sudden appearance of symptoms due to cumulative effects (Grob and Harvey, 1958). Conversely, blood ChE activity can become very low without overt signs or symptoms during chronic exposures to low concentrations of organophosphates. This may be due to a slower rate of recovery of RBC-AChE compared to tissue ChE, or to noncholinesterase-dependent recovery pathways for neural tissue (Grob and Harvey, 1958). Sumerford et al. (1953) reported that orchard workers exposed to organophosphate insecticides had RBC- and plasma-ChE values as low as 15% of normal values without any other signs or symptoms of exposure. Animal studies have demonstrated that chronic exposures to low concentrations of organophosphate insecticides and nerve agents can result in increased tolerance levels (Barnes, 1954; Rider et al., 1952; Dulaney et al., 1985). Similarly, Sumerford et al. (1953) reported increased levels of tolerance to organophosphate insecticides in people living near orchards treated with organophosphate insecticides. Such adaptation may result from increased rates of formation of blood ChE, or from increased rates of detoxification. Additional information on the development of tolerance to organophosphate cholinesterase inhibitors can be found in a review paper by Hoskins and Ho (1992). The blood cholinesterases may, to some degree, provide a protective effect by binding with some fraction of the anticholinesterase compound (Wills, 1972). However, not all nerve agents bind equally well with all cholinesterases. In tests conducted on dogs, Holmstedt (1959) found that GA affected RBC and plasma cholinesterase to a nearly equal degree. In contrast, agent VX preferentially inhibits RBC-AChE (70% compared with about 20% inhibition of plasma ChE) (Sidell and Groff, 1974). Rodents (but not humans) have other enzymes in the blood, termed aliesterases, which can bind organophosphates, thereby reducing the amount available for binding with acetylcholinesterase (Fonnum and Sterri, 1981). Agent GB binds with aliesterases; however, according to Fonnum and Sterri (1981), VX has a quartenary ammonium group which prevents it from being a substrate for aliesterases. The strong specificity of agent VX to AChE may account, in part, for the fact that it is much more acutely toxic than agents GA and GB (Munro et al., 1994).

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 2.2.1 Intra- and Interspecies Variation in Blood Cholinesterase Activity Although blood cholinesterase activity is used as a measure of exposure to organophosphate compounds, baseline activity levels can vary between individuals and between species. According to Wills (1972), both plasma- and RBC-AChE activity are generally lower in women than in men. Sidell and Kaminskis (1975) reported that, for a test population of 22 human subjects, the highest coefficient of variation of RBC-AChE was 4.1% per single subject; the average range of variation was ± 2.1% for men and ± 3.1% for women. In individuals studied for one year, the RBC-AChE activity varied by 11% in men and 16% in women. Yager et al. (1976) reported a 10.0% intra-individual coefficient of variation for RBC-AChE and 14.4% for plasma-ChE. Callaway et al. (1951) estimated that with only one preexposure measurement, the smallest measurable decrease was 15% of the baseline value for RBC-AChE activity and 20% of the baseline for plasma-ChE. A small subpopulation of men and women have a genetic defect causing their blood cholinesterase activity to be abnormally low (Evans et al., 1952; Harris and Whitaker, 1962). For homozygous individuals, the activity can be as low as 8–21% of the normal mean (Bonderman and Bonderman, 1971). Morgan (1989) suggests that these individuals may be unusually sensitive to organophosphate anticholinesterase compounds. Data compiled by Ellin (1981) reveal that the RBC-AChE activity for humans is slightly higher than that for monkeys and much higher than that for rats and other laboratory animals (Table 1). These differences in RBC-AChE activity may affect a species' sensitivity to a particular organophosphate compound. At the same time, the relative amount of plasma cholinesterase and other compounds in the blood that can bind to the organophosphate agents must also be considered. For example, rodents, but not humans, have high levels of aliesterases (AE) in the blood, and these compounds may provide rats and mice with a higher level of resistance to some anticholinesterase compounds (McNamara and Leitnaker, 1971). 2.2.2 Potency of Nerve Agents as Cholinesterase Inhibitors The potency of the anticholinesterase activity of nerve agents and other organophosphates is expressed by the bimolecular rate constant (ki) for the reaction of the phosphate compound with the enzyme and by the molar concentration causing 50% inhibition of the enzyme when tested in vitro (I50). I50 data for several organophosphate nerve agents have been tabulated by Dacre (1984). The relationship between I50 and ki as a function of time (t) is expressed by the following equation (Eto, 1974): (1)

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Table 1. RBC-ChE Activity in Different Species Species RBC-ChE activity (µmol/mL/min) Optimum substratea concentration (M) Human 12.6 2 × 10-3 Monkey 7.1 2 × 10-3 Pig 4.7 1 × 10-3 Goat 4.0 2 × 10-3 Sheep 2.9 2 × 10-3 Mouse 2.4 2 × 10-3 Dog 2.0 2 × 10-2 Guinea pig 2.7 2 × 10-3 Rabbit 1.7 5 × 10-3 Rat 1.7 5 × 10-3 Cat 1.5 5 × 10-3 Source: Ellin, 1981 a Acetylthiocholine iodide concentration for maximum RBC-ChE activity. The pI50 (negative log of the molar concentration causing 50% inhibition) for GD is 9.2 as reported by Dacre (1984). Relative potency of nerve agents can also be expressed in terms of the in vivo dose necessary to produce the same level of cholinesterase inhibition by a specific exposure route. As would be expected, the effectiveness of the agents in inhibiting cholinesterase is closely correlated with their acute toxicity (see Appendix A). 3. TOXICOLOGY 3.1 Introduction Health and environmental impacts of nerve agents and related compounds (organophosphate insecticides) have been reviewed by O'Brien (1960), Matsumura (1976), Dacre (1984), Carnes and Watson (1989), Watson et al. (1989), and Munro et al. (1994). A brief general discussion of the toxicology of nerve agents and related organophosphate pesticides is given below. Nerve agents are acutely toxic by all routes of exposure. Initial symptoms of acute poisoning are fatigue, headache, mild vertigo, weakness, and loss of concentration. Moderate exposures result in miosis and excessive sweating, tearing, and salivation. Acidosis and hyperglycemia may also occur in addition to muscular weakness, muscular twitching, lacrimation, urination, and defecation. Acute poisoning can result in prostration, clonic convulsions (rapid repetitive movements) and tonic convulsions (limbs stretched and rigid) (Matsumura, 1976). Exposures sufficiently high to cause convulsions have resulted

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents The use of the subchronic rat study for developing an oral RfD for GD is complicated by the fact that rodents have a much lower RBC-AChE activity level compared to humans (Ellin, 1981, see Table 1). By itself, this could cause rats to be relatively more sensitive than humans to anticholinesterase compounds; however, the lower RBC-ChE activity may be offset by the presence of aliesterase in rat blood. Aliesterase, which is not present in humans (Cohen et al., 1971), is known to bind to and thereby reduce the toxicity of cholinesterase inhibitors (Fonnum and Sterri, 1981). Other species differences, such as the rates of aging of the nerve agent-ChE complex, the rates of synthesis of plasma cholinesterase in the liver, and the levels of AChE in various parts of the nervous system (see Ivanov et al., 1993) may also result in differences in species' sensitivities. There are insufficient data to determine the relative susceptibilities of humans and rodents to GD; therefore, for the purpose of this assessment, the EPA method will be followed which assumes that humans may be as much as ten times more sensitive to a chemical than laboratory animals. 4.2 Derivation of the Oral RfD for GD The subchronic rat study conducted by Bucci et al. (1992a) is used here to derive an oral RfD for GD. This study is described in detail in section 3.2. Briefly summarized, the results of this study showed statistically significant (p <0.05) decreases in plasma-ChE activity levels in male and female CD rats dosed by gavage once per day, 5 days per week for 13 weeks. There were no definitive dose-related changes in RBC-ChE, and NTE levels were not significantly affected by the GD treatment. The lowest tested dose (17.5 µg/kg/day = 0.0175 mg/kg/day) is considered a LOAEL because of the statistically significant reduction in plasma ChE (relative to controls) and also because the plasma-ChE activity during week 1 was reduced to 39% of baseline in males and 57% of baseline in females. This dose is adjusted to a 7 day/week exposure period by using a factor of 5/7; i.e., 5/7 × 0.0175 mg/kg/day = 0.0125 mg/kg/day. The RfD can then be calculated according to the following formula. (2) where UF1 = 10 (sensitive subpopulations) UF2 = 10 (animal to human extrapolation) UF3 = 3 (although plasma-AChE is not expected to be inhibited at longer exposures, however, an uncertainty factor was incorporated to account for effects possibly unrelated to plasma-AChE inhibition) UF4 = 3 (LOAEL to NOAEL extrapolation; altered plasma-AChE is not overtly toxic) UF5 = 3 (data base incomplete due to lack of chronic oral studies in two species, and studies assessing reproductive/developmental effects) MF = 1 (no additional modifications needed). An uncertainty factor of 10 for sensitive subpopulations is considered necessary because some individuals have a genetic defect causing their blood cholinesterase activity to be abnormally low (Evans et al., 1952; Harris and Whitaker, 1962). These individuals, therefore, may be unusually sensitive to organophosphate anticholinesterase compounds.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents An uncertainty factor of 10 is used for animal-to-human extrapolation because there is no evidence suggesting that humans less sensitive to GD than are laboratory animals. An uncertainty factor of 3 is used to extrapolate from a subchronic to chronic exposure. In the derivation of the oral RfDs for other organophosphate compounds, the EPA has used NOAELs for cholinesterase inhibition following short-term exposures without adjustment for a more prolonged exposure period because of the unlikelihood that the endpoint would change over time (i.e., a subchronic-to-chronic UF of 1 was used). In addition, animal data indicate that maximum ChE inhibition may occur 30–60 days or more after exposure begins, after which it levels off or even shows recovery. In the Bucci et al. (1992a) study, both plasma and RBC-AChE levels exhibited signs of recovery at week 13, especially for the lower doses (Tables 5–8). Therefore, increased ChE inhibition is not expected to occur at longer exposure periods. However, an uncertainty factor of 3 is used because studies are not available to verify that adverse effects would not occur following chronic exposures. A LOAEL-to-NOAEL uncertainty factor of 3 is used instead of 10 because the endpoint, cholinesterase inhibition, was not associated with signs of toxicity. The database for GD lacks chronic oral studies in two species, and studies assessing reproductive/developmental effects. Because studies on other organophosphate cholinesterase inhibitors, including a multigeneration study on agent VX, indicate that reproductive/developmental effects are unlikely, a full uncertainty factor of 10 is not warranted. Therefore, (3) (4) (5) 4.3 Comparison of RfD with Toxicity Data Only limited data regarding exposure to GD are available for comparison to the proposed RfD. An oral LD50 of 5–20 mg/kg for humans was estimated by Somani et al., (1992). The proposed RfD of 0.005 µg/kg is considerably lower than this value. The proposed RfD is more than 2 orders of magnitude below the ED50 dose (0.97 µg/kg) shown to produce performance decrements in rhesus monkeys after five consecutive days of dosing (Blick et al., 1994). Nieminen et al. (1990) reported behavioral effects concurrent with reduced blood AChE levels in rats given single i.p. injections of GD at doses of 4 or 20 µg/kg.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 5. CARCINOGENICITY ASSESSMENT FOR GD The potential carcinogenicity of agent GD cannot be determined. Data are inadequate for performing a quantitative assessment of agent GD.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 6. REFERENCES CITED Abbrecht, P.H., R.R. Kyle and H.J. Bryant. 1989. Nebulized atropine for treatment of organophosphate toxicity. USAMRDC Med. Def. Biosci. Rev. pp. 201–205. (cited in Somani et al., 1992). Anderson, D.R., L.W. Harris and W.J. Lennox. 1989. Subacute vs. acute physostigmine pretreatment against soman poisoning. USAMRDC Med. Def. Biosci. Rev. pp. 511–514. (cited in Somani et al., 1992). Albuquerque, E.X., S.S. Deshpande, M. Kawabuchi, Y. Aracava, M. Idriss, D.L. Rickett, and A.F. Boyne. 1985. Multiple actions of anticholinesterase agents on chemosensitive synapses: Molecular basis for prophylaxis and treatment of organophosphate poisoning. Fund. Appl. Toxicol. 5:S182–S203. Barnes, J.M. 1954. Organo-phosphorus insecticides. The toxic action of organo-phosphorus insecticides in mammals. Chem and Ind. January 2, 1954, pp. 478–480. Baze, W.B. 1993. Soman-induced morphological changes: An overview in the non-human primate. J. Appl. Toxicol. 13: 173–177. Blick, D.W., F.R. Weatherby, Jr., G.C. Brown and M.R. Murphy. 1994. Behavioral toxicity of anticholinesterases in primates: Effects of daily repeated exposure. Pharmacol. Biochem. Behav. 48: 643–649. Bonderman, R.P. and D.P. Bonderman. 1971. A titrimetric method for differentiating between atypical and inhibited human serum pseudocholinesterase. Arch. Environ. Health 22:578–581. (Cited in Hayes, 1982) Boskovic, B. 1981. The treatment of soman poisoning and its perspectives. Fundam. Appl. Toxicol. 1: 203–213. Bucci, T.J., R.M. Parker and P.A. Gosnell. 1992a. Toxicity Studies on Agents GB and GD (Phase II), 90 Day Subchronic Study of GD (Soman) in CD-Rats. Final Report. Prepared for U.S. Army Biomedical Research and Development Laboratory, Fort Detrick, MD. FDA 224-85-0007. Bucci, T.J., R.M. Parker and P.A. Gosnell. 1992b. Toxicity Studies on Agents GB and GD (Phase II): Delayed Neuropathy Study of Soman in SPF White Leghorn Chickens. Final Report. Prepared for U.S. Army Biomedical Research and Development Laboratory, Fort Detrick, MD. Bucci, T.J., R.M. Parker, J.A. Crowell, J.D. Thurman and P.A. Gosnell. 1992c. Toxicity Studies on Agent GA (Phase II): 90 Day Subchronic Study of GA (Tabun) in CD Rats. Final Report. Prepared for the U.S. Army Biomedical Research and Development Laboratory, Fort Detrick, MD. DTIC AD-A258020. Burchfiel, J.L., F.H. Duffy and V.M. Sim. 1976. Persistent effects of sarin and dieldrin upon the primate electroencephalogram. Toxicol. Appl. Pharmacol. 35: 365–369. Callaway, S., D.R. Davies and J.P. Rutland. 1951. Blood cholinesterase levels and range of personal variation in a healthy adult population. Br. Med. J. 2:812–816. Carnes, S.A. and A.P. Watson. 1989. Disposing of the U.S. chemical weapons stockpile: An approaching reality. JAMA 262:653–659.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents APPENDIX A Comparison of RfDs, ChE Inhibition and Toxicity Data for GA, GB, GD and VX Endpoint GA (µg/kg/day) GB (µg/kg/day) GD (µg/kg/day) VX (µg/kg/day) Ref. RfD 0.04 0.02 0.004 0.0006 This report Estimated no-effect level for RBC-AChE inhibition - 1.0 - 0.24 GBd VXa 27–33% inhibition of RBC-AChE in humans/oral dose - 2.3 (3 days) - 0.2-2.0 GB - Grob and Harvey, 1958; VX-this report RBC-AChE inhibition in humans/i.v. dose - - 1.5-2.0 (30%) 1.0 (50%) DA, 1974; Sidell and Groff, 1974 50–60% RBC-AChE inhibition in humans/oral dose - 10 - 2.4 GB - Grob and Harvey, 1958; VX-Sidell and Groff, 1974 50% brain ChE inhibition in vitro 1.5 × 10-8 (c) 0.3 × 10-8 (c) - - Grob and Harvey, 1958 Acute toxic effects in humans/oral dose - 20–30 - 2–4.5 GB - Thienes and Haley 1972; Grob and Harvey, 1958; VX-Sidell and Groff, 1974 human oral LD50 (estimated) 25–50b 5–20b 5–20 3–10b Somani et al., 1992 rat oral LD50 3700 870–1060 600 400 77–128 DA, 1974 Grob & Harvey, 1958 monkey i.v. LD50 50 20 - 6–11 DA, 1974 rat i.v. LD50 70 45–63 50 6.9–10.1 Dacre, 1984 rat i.p. LD50 490, 800 250 218 - 37–55 DA, 1974 RTECS, 1995 a Based on ratio of oral to i.v. doses (2.4 and 1.0 µg/kg, respectively) required for 50% RbC-ChE inhibition and the estimated i.v. no effect dose of 0.1 µg/kg b Values were estimated from animal data. c Molar concentration d Estimated from RBC-ChE50 values for GB and VX.