Appendix A
Health Risk Assessment for The Nerve Agent GA



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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Appendix A Health Risk Assessment for The Nerve Agent GA

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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 THE NERVE AGENT GA DRAFT REPORT September 1996 (editorial corrections made April 1997) Prepared for U.S. Department of the Army Army Environmental Center under Interagency Agreement No. 1769-1769-A1 Prepared by Life Sciences Division OAK RIDGE NATIONAL LABORATORY* OAK RIDGE, TENNESSEE 37831 Submitted to Material/Chemical Risk Assessment Working Group Advisory and Coordinating Committee Environmental Risk Assessment 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 GA (CAS No. 77-81-6). 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. Dennis M. Opresko, 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. External review of the toxicity data was provided by Dr. Thomas J. Bucci, Integrated Services, White Hall, AR and Dr. I.K Ho of the U. of Mississippi Medical Center, Jackson MS. External review of the derivation of the RfDs was provided by Drs. Michael Dourson and Susan Velazquez of Toxicology Excellence for Risk Assessment, Cincinnati, OH, and Dr. William Hartley of Tulane Medical Center, New Orleans LA. Additional reviews were provided by Mr. Joe King, Dr. Jack Heller, Ms. Veronique Hauschild, Ms. Bonnie Gaborek, Mr. Maurice Weeks, Maj. Robert Gum, and Mr Kenneth Williams of the U.S Army.

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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     2. Mechanism of Action   2     2.1 Effects of Organophosphate Agents on the Nervous System   3     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   6     3. Toxicology   6     3.1 Introduction   6     3.2 Acute Toxicity   7     3.3 Subchronic Toxicity   7     3.4 Chronic Toxicity   11     3.5 Nervous System Toxicity   11     3.6 Developmental and Reproductive Effects   11     3.7 Carcinogenicity   12     3.8 Genotoxicity   12     4. Oral Reference Dose for GA   13     4.1 Cholinesterase Inhibition as an RfD Endpoint   13     4.2 Derivation of the Oral RfD   14     4.3 Overall Confidence in the Oral RfD   17     4.4 Comparison of the RfD with Human Toxicity Data   17     5. Carcinogenicity Assessment   17     6. References Cited   18     Appendix A. Comparison of RfDs, ChE Inhibition and Toxicity Data for GA, GB, GD and VX   A-1     Appendix B. Statistical Analysis of RBC-AChE Inhibition in Rats   B-1     Appendix C. Statistical Analysis of Plasma-ChE Inhibition in Rats   C-1

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents LIST OF TABLES Table 1.   RBC-ChE activity in different species   5 Table 2.   LD50 values for agent GA   8 Table 3.   RBC-AChE levels in 90-day subchronic rat study using agent GA   9 Table 4.   Plasma-ChE levels in 90-day subchronic rat study using agent GA   10

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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). GA contains a cyanide substituent group (VX contains a sulfur group and GB a fluorine group). The chemical synonyms, Chemical Abstract Service (CAS) and Army identification numbers (DA, 1974, 1992; Dacre, 1984), and chemical formula for GA are as follows: Dimethylphosphoramidocyanidic acid, ethyl ester; Dimethylaminoethoxy-cyanophosphine oxide; Dimethylamidoethoxyphosphoryl cyanide; Ethyl N, N-dimethylphosphoramidocyanidate; Ethyl N, N-dimethylaminocyanophosphate Ethyl dimethylphosphoramidocyanidate; Ethyl dimethylamidocyanophosphate; Ethylphosphorodimethylamidocyanidate; Tabun; CAS No. 77-81-6; Edgewood Arsenal No. 1205 1.1. PHYSICAL/CHEMICAL PROPERTIES Agent GA is a colorless to brown-colored liquid with a molecular weight of 162.1 (DA, 1974; MacNaughton and Brewer, 1994); it has a vapor density of 5.6 (air = 1) and a liquid density of 1.08 g/mL at 25°C (DA, 1974). The vapor pressure of GA is 0.07 mm Hg at 25°C; its solubility in distilled water is 9.8 g per 100 g at 25°C and 7.2 g per 100 g at 20°C (DA, 1974). 1.2. ENVIRONMENTAL FATE 1.2.1 Air The vapor pressure for GA is 0.07 mm Hg at 25°C indicating a moderate potential for volatilization. A vapor concentration of 610 mg/m3 has been reported for a temperature of 25°C (DA, 1974) (although not adequately described in the reference, this presumably is the saturation concentration above a pure liquid). 1.2.2 Water

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents GA has a water solubility of 50–100 mg/L (MacNaughton and Brewer, 1994)); therefore, it is a potential water contaminant. However, because it is subject to hydrolysis, it is not expected to be very persistent in aqueous systems. The half-life of GA is less than 10 min at pH levels greater than 9, 2–3 hr at pH 8–9, and about 6 hr at a pH of 4 (MacNaughton and Brewer, 1994). The Henry's Law Constant for GA has been estimated to be 1.3 × 10-6 atm m3/mol (MacNaughton and Brewer, 1994), indicating that GA may volatilize slowly from water. 1.2.3 Soil Although a soil half-life of 1 to 1.5 days has been reported for GA (DA, 1974), information was not provided on the temperature, pH, or moisture content and other environmental conditions for which this estimate was made. The volatility potential (slope of the vapor pressure vs. concentration in soil organics) of GA is 2.4 × 10-7 mm Hg/mg/kg and its air-soil partition coefficient (for a soil density of 1.4 g/cm3) of 1 × 10-4 mg/m3 (MacNaughton and Brewer, 1994), indicate that GA will evaporate from soil into the air. Results of a field trial with GA showed 10% evaporation in 0.27 hours and 90% evaporation in 4.66 hours (Morrill et al., 1985). Binding of GA to soil organics is likely to be limited considering the relatively low log Kow of 0.11 and low Koc values of 25 (MacNaughton and Brewer, 1994); therefore, a potential exists for leaching and groundwater contamination. MacNaughton and Brewer (1994) calculated a leaching index of 2 for GA, (i.e., the number of leachings required to reduce the GA soil concentration to one-tenth of the original amount, assuming that for each leaching one kilogram of soil is in equilibrium with one liter of water). However, the amount of GA reaching ground water is likely to be limited by hydrolysis. 2. MECHANISM OF ACTION Nerve agents are inhibitors of acetylcholinesterase (AChE), an enzyme responsible for deactivating the neurotransmitter acetylcholine 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).

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 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. Although there is the potential for nerve agents to have direct toxic effects on the nervous system, there is no evidence that such effects occur in humans at doses lower than those causing cholinesterase inhibition. For the purpose of evaluating potential health effects, inhibition of blood 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). Both RBC-AChE and plasma-ChE activity have been used as bioindicators of potential toxic effects. There is some 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),

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 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-AChE values as low as 13% of preexposure values without any other signs or symptoms of toxicity. 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 (1951) 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 to 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 quaternary 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 (see Appendix A). 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 activity and 14.4% for plasma-ChE activity. Callaway et al. (1951) estimated that with only one pre-exposure measurement, the smallest measurable decrease was 15% of the baseline value for RBC-AChE activity and 20% of the baseline for plasma-ChE activity. 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 Whittaker, 1962). For homozygous individuals, the activity can be as low as 8–21% of the normal mean (Bonderman and Bonderman, 1971).

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents at a concentration of 50 mg-min/m3 (Reutter, unpublished data). The LCt50 is 135 mg min/m3 for time periods of 0.5–2.0 min (DA, 1974). DHHS (1988) has set an inhalation maximum control limit of 0.000003 mg/m3 for the general public (72 hr time-weighted average). 5. CARCINOGENICITY ASSESSMENT The potential carcinogenicity of GA cannot be determined. Data are inadequate for performing a quantitative assessment of agent GA.

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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 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. 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) Bucci, T.J., R.M. Parker, J.A. Crowell, J.D. Thurman and P.A. Gosnell. 1992. 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. Bucci, T.J., J.D. Fikes, R.M. Parker, K.H. Denny and J.C. Dacre. 1993. Developmental Toxicity Study (Segment II Teratology) of Tabun in CD Rats and in New Zealand White Rabbits. National Center for Toxicological Research, Final Report Nos. E515 and E516. Prepared for the U.S. Army Medical Research and Development Command, Fort Detrick, MD. 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. (Cited in Hayes, 1982) Carnes, S.A. and A.P. Watson. 1989. Disposing of the U.S. chemical weapons stockpile: An approaching reality. JAMA 262:653–659. Crook, J.W., P. Hott, E.J. Owens, E.G. Cummings, R.L. Farrand, and A.E. Cooper. 1983. The Effects of Subacute Exposures of the Mouse, Rat, Guinea Pig, and Rabbit to Low-Level VX Concentrations. Technical Report ARCSL-TR-82038, AD BO86567L. Chemical Systems Laboratory, U.S. Army Armament Research and Development Command, Aberdeen Proving Ground, MD. DA (U.S. Department of the Army). 1974. Chemical Agent Data Sheets, vol. 1. Edgewood Arsenal Special Report, EO-SR 74001. Defense Tech. Inform. Center, Alexandria, VA. DA (U.S. Department of the Army). 1992. Material Safety Data Sheets: GA. Edgewood Research, Development and Engineering Center, Aberdeen Proving Ground, MD. Dacre, J.C. 1984. Toxicology of some anticholinesterases used as chemical warfare agents - a review. In: Cholinesterases: Fundamental and Applied Aspects, M. Brzin, E.A. Barnard and D. Sket, eds., Walter de Gruyter, New York. pp. 415–426. DHHS (U. S. Department of Health and Human Services, Centers for Disease Control). 1988. Final

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents recommendations for protecting the health and safety against potential adverse effects of long-term exposure to low doses of agents: GA, GB, VX, Mustard Agent (H, HD, T), and Lewisite (L). Federal Register 53:8504–8507. Duffy, F.H., J.L. Burchfiel, P.H. Bartels, et al. 1979. Long-term effects of an organophosphate upon the human electroencephalogram. Toxicol. Appl. Pharmacol. 47:161–176. Duffy, F.H. and J.L. Burchfiel. 1980. Long-term effects of the organophosphate sarin on EEGs in monkeys and humans. Neurotoxicol. 1:667–689. Dulaney, M.D., B. Hoskins and I.K. Ho. 1985. Studies on low dose sub-acute administration of soman, sarin, and tabun in the rat. Acta Pharmacol. Toxicol. 57:234–241. Ellin, R.I. 1981. Anomalies in Theories and Therapy of Intoxication by Potent Organophosphorus Anticholinesterase Compounds. Special Publication USABML-SP-81-003, AD A101364. U.S. Army Medical Research and Development Command, Biomedical Laboratory, Aberdeen Proving Ground, MD. Eto, M. 1974. Organophosphorus Pesticides: Organic and Biological Chemistry. CRC Press, Cleveland, OH. pp. 123–231. Evans, F.T., P.W.S. Gray, H. Lehmann and E. Silk. 1952. Sensitivity to succinylcholine in relation to serum cholinesterase. Lancet 1:1129–1230. (Cited in Hayes, 1982). Fonnum, F. and S.H. Sterri. 1981. Factors modifying the toxicity of organophosphorous compounds including soman and sarin. Fund. Appl. Toxicol. 1:143–147. Gershon, J.L. and F.H. Shaw. 1961. Psychiatric sequelae of chronic exposure to organophosphorus insecticides. Lancet (June 24, 1961): 1371–1374. Goldman, M., B.W. Wilson, T.G. Kawakami, L.S. Rosenblatt, M.R. Culbertson, J.P. Schreider, J.F. Remsen, and M. Shifrine. 1988. Toxicity Studies on Agent VX. Final Report from the Laboratory for Energy-Related Health Research to U.S. Army Medical Research and Development Command, Fort Detrick, MD. AD A201397. Grob, D. and J.C. Harvey. 1958. Effects in man of the anticholinesterase compound Sarin (isopropyl methyl phosphonofluoridate). J. Clin. Invest. 37(1):350–368. Halbrook, R.S., L.R. Shugart, A.P. Watson, N.B. Munro and R.D. Linnabary. 1992. Characterizing biological variability in livestock blood cholinesterase activity for biomonitoring organophosphate nerve agent exposure. J. Amer. Vet. Med. Assoc. 201:714–725. Harris, H. and M. Whittaker. 1962. The serum cholinesterase variants. Study of twenty-two families selected via the ''intermediate" phenotype. Ann. Hum. Genet. 26:59–72. (Cited in Hayes, 1982) Hayes, W.J. 1982. Pesticides Studied in Man. William and Wilkins, Baltimore, MD.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Henderson, J.D., R.J. Higgins, L. Rosenblatt and B.W. Wilson. 1989. Toxicity Studies on Agent GA: Delayed Neurotoxicity - Acute and Repeated Exposures to GA (Tabun). Final Report, U.S. Army Medical Research and Development Command, Fort Detrick, MD. AD A219457. Henderson, J.D., R.J. Higgins, J.C. Dacre, et al. 1992. Neurotoxicity of acute and repeated treatments of tabun, paraoxon, diisopropyl fluorophosphate and isofenphos to the hen. Toxicology 72: 117–129. Holmstedt, B. 1951. Synthesis and pharmacology of dimethylamidoethoxyphosphoryl cyanide (Tabun) together with a description of some allied anticholinesterase compounds containing the NP bond. Acta Physiol. Scand. 25 (Suppl. 90):1–120. Holmstedt, B. 1959. Pharmacology of organophosphorus cholinesterase inhibitors. Pharmacol. Reviews 11:567–688. Hoskins, B. and I.K. Ho. 1992. Tolerance to organophosphate cholinesterase inhibitors. In: Organophosphates: Chemistry, Fate and Effects, J.E. Chambers and P.E. Levi, eds. Academic Press, New York, pp. 285–297. Ivanov, P., B. Georgiev, K. Kirov, L. Venkov. 1993. Correlation between concentration of cholinesterase and the resistance of animals to organophosphorus compounds. Drug Chem. Toxicol. 16:81–99. Jimmerson, V.R. T-M. Shih and R.B. Mailman. 1989. Variability in soman toxicity in the rat: Correlation with biochemical and behavioral measures. Toxicology 57:241–254. Johnson, M.K., J.L. Willems, H.C. De Bisschop, et al. 1988. High doses of soman protect against organophosphorus-induced polyneuropathy but tabun does not. Toxicol. Appl. Pharmacol. 92:34–41. (Cited in Munro et al., 1994) Lotti, M. and M.K. Johnson. 1978. Neurotoxicity of organophosphorus pesticides: predictions can be based on in vitro studies with hen and human enzymes. Arch. Toxicol. 41:215–221. (Cited in Munro et al., 1994 ) MacNaughton, M.G. and J.H. Brewer. 1994. Environmental Chemistry and Fate of Chemical Warfare Agents. Southwest Research Institute, San Antonio, TX Matsumura, F. 1976. Toxicology of Insecticides. Plenum Press, New York, NY. pp. 17–46, 64–78, 142–152, 403–444, 462–464. McNamara, B.P. and F. Leitnaker. 1971. Toxicological Basis For Controlling Emission of GB Into the Environment. EASP 100-98, AD 914271L. U.S. Army, Medical Research Laboratory, Edgewood Arsenal, Aberdeen Proving Ground, MD. Marquis, J.K. (ed.). 1988. Cholinesterase inhibition as an indication of adverse toxicologic effects. Review draft (June, 1988). Prepared for the Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. Metcalf, D.R. and J.H. Holmes. 1969. EEG, psychological, and neurological alterations in humans with organophosphorus exposure. Ann. N.Y. Acad. Sci. 357–365.

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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 800–1060 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.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Appendix B STATISTICAL ANALYSIS OF GA-INDUCED RBC-AChE INHIBITION IN RATS (Bucci et al., 1992) GA - RBC-AChE Inhibition in Female Rats (ANOVA and Dunnett's)   Week I.P. Dosea (µg/kg/day) -1 1 3 7 13 0   ns/ ns/ ns/ ns/ 28.13 _/ns S/ns ns/ns S/ns ns/ns 56.25 _/ns S/ns ns/ns S/ns ns/ns 112.5 _/ns S/ns S/ns S/ns ns/ns a Six animals/dose group b Comparison to pre-exposure value (week -1)/comparison to control (0 µg/kg/day) value. ns. Not statistically significant. S. Statistically significant at p <0.05. GA - RBC-AChE Inhibition in Male Rats (ANOVA and Dunnett's)   Week I.P. Dosea (µg/kg/day) -1 1 3 7 13 0   ns/ ns/ S/ ns/ 28.13 _/ns S/ns ns/ns ns/ns ns/ns 56.25 _/ns S/ns ns/ns ns/ns ns/ns 112.5 _/ns ns/ns ns/ns ns/ns ns/ns a Six animals/dose group b Comparison to pre-exposure value (week -1)/comparison to control (0 µg/kg/day) value. ns. Not statistically significant. S. Statistically significant at p <0.05.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Appendix C STATISTICAL ANALYSIS OF GA-INDUCED PLASMA-ChE INHIBITION IN RATS (Bucci et al., 1992) GA - Plasma-ChE Inhibition in Female Rats (ANOVA and Dunnett's)   Week I.P. Dosea (µg/kg/day) -1 1 3 7 13 0   ns/ ns/ ns/ ns/ 28.13 _/ns ns/S ns/S ns/S S/ns 56.25 _/ns ns/S ns/S ns/S ns/ns 112.5 _/ns ns/S ns/S ns/S ns/ns a Six animals/dose group b Comparison to pre-exposure value (week-1)/comparison to control (0 µg/kg/day) value. ns. Not statistically significant. S. Statistically significant at p <0.05. GA - Plasma-ChE Inhibition in Male Rats (ANOVA and Dunnett's)   Week I.P. Dosea (µg/kg/day) -1 1 3 7 13 0   ns/ ns/ ns/ ns/ 28.13 _/ns ns/ns ns/ns ns/ns ns/ns 56.25 _/ns S/ns S/S S/S S/ns 112.5 _/ns S/S S/S S/S ns/ns a Six animals/dose group b Comparison to pre-exposure value (week -1)/comparison to control (0 µg/kg/day) value. ns. Not statistically significant. S. Statistically significant at p <0.05.

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