Appendix B
Health Risk Assessment for The Nerve Agent GB



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

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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 GB 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 GB (CAS No. 107-44-8). 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   2     2. Mechanism of Action   3     2.1 Effects of Organophosphate Agents on the Nervous System   3     2.2 Effect on Blood Cholinesterases   4     2.2.1 Intra- and Interspecies Variation in Blood Cholinesterase Activity   5     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   9     3.4 Chronic Toxicity   11     3.5 Nervous System Toxicity   13     3.6 Developmental and Reproductive Effects   14     3.7 Carcinogenicity   15     3.8 Genotoxicity   15     4. Oral Reference Dose for GB   16     4.1 Cholinesterase Inhibition as an RfD Endpoint   16     4.2 Derivation of the Oral RfD   17     4.3 Overall Confidence in the Oral RfD   19     4.4 Comparison of the RfD with Human Toxicity Data   19     5. Carcinogenicity Assessment   19     6. References Cited   21     Appendix A. Comparison of RfDs, ChE Inhibition and Toxicity Data for GA, GB, GD and VX   A-1     Appendix B. Statistical Analysis of GB-Induced ChE Inhibition in Rats   B-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.   Lethality data for agent GB   8 Table 3.   RBC-ChE levels in 90-day subchronic study of GB type I in CD rats   10 Table 4.   RBC-ChE levels in 90-day subchronic study of GB type II in CD rats   10 Table 5.   Plasma-ChE levels in 90-day subchronic study of GB type II in CD rats   11 Table 6.   Sacrifice schedule for GB chronic study   12 Table 7.   Incidence of tracheitis in colony rats in GB chronic study   13 Table 8.   Comparison of RfD with human toxicity data for GB   20

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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). GB contains a fluorine 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, 1992; Dacre, 1984), and chemical formula for GB are as follows: Phosphonofluoridic acid, methyl-, 1-methylethyl ester Phosphonofluoridic acid, methyl-, isopropyl ester Isopropoxymethylphosphoryl fluoride; Isopropyl methylfluorophosphate; Isopropyl methanefluorophosphonate; O-Isopropyl methylphosphonofluoridate; O-Isopropyl methylisopropoxyfluorophosphine oxide; Isopropyl-methyl-phosphoryl fluoride: Isopropoxymethylphosphonyl fluoride; Methylphosphonofluoridic acid isopropyl ester; Methylfluorophosphonic acid, isopropyl ester; Methylphosphonofluoridic acid 1-methylethyl ester; Methylisopropoxyfluorophosphine oxide; Sarin CAS No. 107-44-8; Edgewood Arsenal No. 1208 1.1 PHYSICAL/CHEMICAL PROPERTIES Agent GB is a colorless liquid with a molecular weight of 140.1 (DA, 1974, MacNaughton and Brewer, 1994); it has a vapor density of 4.8 (air = 1) and a liquid density of 1.09 g/mL at 25°C (DA, 1974). The vapor pressure of GB is 2.9 mm Hg at 25°C. It is miscible with water and readily soluble in organic solvents (DA, 1974).

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 1.2. ENVIRONMENTAL FATE 1.2.1. Air GB is very volatile with a vapor pressure of 2.9 mm Hg at 2519MMacNaughton and Brewer, 1994). A vapor concentration of 22 g/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). No information was found on the atmospheric half-life of GB. 1.2.2 Water GB is completely miscible with water (DA, 1974). Its rate of hydrolysis is dependent on temperature, pH, and other water quality parameters (Epstein, 1974; Morrill et al., 1985; Clark, 1989). At 20°C, the half-life ranges from 461 hr at pH 6.5 to 46 hr at pH 7.5. At 25°C, the half-life is 237 hr at pH 6.5 and 24 hr at pH 7.5. GA is much more persistent at low temperature; at 0°C, its half-life is 8,300 hours at pH of 6.5. The rate of hydrolysis under natural conditions is accelerated by the presence of ions (dissolved solids) in solution. Metal cations such as copper and manganese in seawater increase the rate of hydrolysis (Epstein, 1974). Based on an estimated Henry's Law Constant of 5.4 × 10-7 atm m3/mol (MacNaughton and Brewer, 1994), evaporation of GB from water is expected to be slow. 1.2.3 Soil According to Morrill et al. (1985), evaporation is the primary mechanism for the loss of GB from soil, and this is supported by the estimated volatility potential (slope of the vapor pressure vs. concentration in soil organics) of 4.9 × 10-8 mm Hg/mg/kg and by the air-soil partition coefficient of 135 × 10-5 mg/m3 (for a soil density of 1.4 g/cm3) as reported by MacNaughton and Brewer (1994). In a field test conducted in Finland detectable concentrations of GB (>1 pg/dm3) were found in the air for up to 9 days following application of 10 mg of GB over a 10 × 10 meter area of moss (temperature 2.5–8 °C, humidity 60–100%, wind speed 1–10 m/s) (Sanches et al., 1993). Studies conducted with soil samples from Dugway Proving Ground and Edgewood Arsenal showed that 90% of GB added to soil and maintained in closed containers at room temperature (20–25°C) was lost in the first 5 days (Small, 1984). Binding of GB to soil organics is likely to be limited considering the relatively low log Kow of 0.72 and low Koc value of 59 (MacNaughton and Brewer, 1994); therefore, there is a potential for leaching and groundwater contamination. MacNaughton and Brewer (1994) calculated a leaching index of 3.7 for GB, (i.e., the number of leachings required to reduce the GB 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 reaching ground water is likely to be limited by hydrolysis.

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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 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. 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

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents doses when the animal is protected by antidotes 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). RBC-ChE 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 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), and only slightly different (3 × 10-9 mol/L and 3.3 × 10 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. 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 may result in a sudden appearance of signs and 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-ChE compared to tissue ChE, or to a noncholinesterase-dependent recovery pathway 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 average preexposure levels without any other signs or symptoms of toxicity. Animal studies have demonstrated that chronic exposures to low concentrations of organophosphate insecticides can also 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 subject to insecticide applications. 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 and other esterases 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. Agent GB inhibits both RBC-ChE (80–100%) as well as plasma-ChE (30–50%) (Grob and Harvey, 1958). In contrast, agent VX preferentially inhibits RBC-ChE (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).

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Therefore, (3) (4) (5) 4.3 Overall Confidence in the Oral RfD Study: High Data Base: Medium RfD: Medium The principal study was well-designed and well-conducted, used a relevant exposure pathway, and examined the appropriate toxicological endpoints. The data base for GB also contains a second oral subchronic study in rats, chronic inhalation studies in rats, mice and dogs, teratology studies in rats and rabbits, and delayed neuropathy studies in mice and chickens. Deficiencies in the data base consist primarily of a lack of a multi-generational reproductive toxicity study, and a standard toxicity study in a second species. Consequently, the overall confidence in the RfD is medium. 4.4 Comparison of the RfD with Human Toxicity Data The RfD is compared to the available human toxicity data in Table 8. One study in humans indicated that an oral dose of 2.3 µg/kg/day for three days resulted in 27 and 33% RBC-AChE inhibition but no toxic effects. This dose is about 115 times greater than the derived RfD. For an adverse effect level (i.e., mild toxic effect at 29 µg/kg/day; Grob and Harvey, 1958), the ''margin of safety" would be about 10 times greater than that for the 27–33% RBC-AChE inhibition. 5. CARCINOGENICITY ASSESSMENT The potential carcinogenicity of GB cannot be determined; however, limited data from animal inhalation studies suggest that agent GB is not carcinogenic (see Section 3.7). The results of mutagenicity assays on bacteria, in vitro tests on mammalian cell cultures, and in vivo studies on mice (see Section 3.8) indicate that GB is not genotoxic or mutagenic. These data provide supporting evidence that GB is not likely to be carcinogenic.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Table 8. Comparison of RfD with Human Toxicity Data for GB Dose (µg/kg) Exposure Route Endpoint References 0.02 oral RfD - no inhibition of RBC-AChE This report 2 oral excessive dreaming Thienes and Haley, 1972 2.3 oral; average daily dose for three days RBC-AChE reduced 27 and 33%, but no toxic effects Grob and Harvey, 1958 10 oral 50% inhibition of AChE Grob and Harvey, 1958 20 oral insomnia, withdrawal, depression Thienes and Haley, 1972 22 oral mild toxic effects, anorexia, nausea, hearburn Grob and Harvey, 1958 29 oral; average daily dose for three days mild toxic effects Grob and Harvey, 1958 30 oral moderate toxic effects Grob and Harvey, 1958 34 oral; average daily dose for three days moderate toxic effects; > 90% reduction in RBC-AChE activity Grob and Harvey, 1958 140 oral Estimated lethal oral dose Grob and Harvey, 1958

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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, et al. 1991. Toxicity Studies on Agents GB and GD (Phase II), 90 Day Subchronic Study of GB (Sarin Type I) in CD-Rats. Final Report. FDA 224-865-0007. Prepared for U.S. Army Biomedical Research and Development Laboratory, Fort Detrick, MD. DTIC AD-A248617. Bucci, T.J. and R.M. Parker. 1992. Toxicity Studies on Agents GB and GD (Phase II), 90 Day Subchronic Study of GB (Sarin Type II) in CD-Rats. Final Report. Prepared for the U.S. Army Biomedical Research and Development Laboratory, Fort Detrick, MD. DTIC AD-A248618. Bucci, T.J., R.M. Parker and P.A. Gosnell. 1992a. Delayed Neuropathy Study of Sarin, Type II, in SPF White Leghorn Chickens. Technical Report. Prepared by the National Center for Toxicological Research, Jefferson, AK, for U.S. Army Biomedical Research and Development Laboratory, Fort Detrick, MD. NTCR Rept Nos. 478, 479. Bucci, T.J., R.M. Parker, J.A. Crowell, J.D. Thurman and P.A. Gosnell. 1992b. 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. Burchfiel, J.L. and F.H. Duffy. 1982. Organophosphate neurotoxicity: chronic effects of sarin on the electroencephalogram of monkey and man. Neurobehav. Toxicol. Teratol. 4: 767–778. 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. Clark, D.N. 1989. Review of Reactions of Chemical Agents in Water. AD-A213 287, Defense Technical Information Center. Cohen, E.M., P.J. Christen and E. Mobach. 1971. The inactivation by oximes of Sarin and Soman in plasma from various species. I. The influence of diacetylmonoxime on the hydrolysis of Sarin. J.A. Cohen memorial issue. North-Holland Publishing Company, Amsterdam. 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: GB. Edgewood Research, Development and Engineering Center, Aberdeen Proving Ground, MD.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 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. Davies, D.R., P. Holland and M.J. Rumens. 1960. The relationship between the chemical structure and neurotoxicity of alkyl organophosphorus compounds. Brit. J. Pharmacol. 15:271–278. Davies, D.R. and P. Holland. 1972. Effect of oximes and atropine upon the development of delayed neurotoxic signs in chickens following poisoning by DFP and sarin. Biochem. Pharmacol. 21:3145–3151. Denk, J.R. 1975. Effects of GB on Mammalian Germ Cells and Reproductive Parameters. EB-TR-74087. (Cited in Weimar et al., 1979) DHHS (U.S. Department of Health and Human Services, Centers for Disease Control). 1988. Final 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(50):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. Epstein, J. 1974. Properties of GB in water. J. Am. Water Works Assoc. 66:31–37. 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 organophosphorus 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., A.K. Klein, T.G. Kawakami and L.S. Rosenblatt. 1987. Taxicity Studies on Agents GB and GD. Final Report from the Laboratory for Energy-Related Health Research to U.S. Army Medical Research and Development Command, Fort Detrick, MD. AD A187841 . 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. Goldstein, B.D. D. R. Fincher and J.R. Searle. 1987. Electrophysiological changes in the primary sensory neuron following subchronic soman or sarin: alterations in sensory receptor function. Toxicol. Appl. Pharmacol. 9:55–64.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Goldstein, B.D. 1989. Changes in spinal cord reflexes following subchronic exposure to soman and sarin. Toxicol. Lett. 47:1–8. Gordon, J.J., R.H. Inns, M.K. Johnson, et al. 1983. The delayed neuropathic effects of nerve agents and some other organophosphorus compounds. Arch. Toxicol. 52:71–82. (Cited in Munro et al., 1994) 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) Heston, W.E. 1942. Inheritance of susceptibility to spontaneous pulmonary tumors in mice. J. Natl. Cancer Inst. 3:79–82. Heston, W.E. and W.D. Levillain. 1953. Pulmonary tumors in strain A mice exposed to mustard gas. Proc. Soc. Exp. Biol. 82:457–460. 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. Husain, K., R. Vijayaraghavan, S.C. Pant, et al. 1993. Delayed neurotoxic effect of Sarin in mice after repeated inhalation exposure. J. Appl. Toxicol. 13:143–145. 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. LaBorde, J.B. and H.K. Bates. 1986. Developmental Toxicity Study of Agent GB-DCSM Types I and II in CD Rats and NZW Rabbits. Final Report. National Center for Toxicological Research, FDA, Jefferson, AR. Prepared for U.S. Army Medical Research and Development Command, Fort Detrick, 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. 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. McLeod, C.G. 1985. Pathology of nerve agents: perspectives on medical management. Fund. Appl. Toxicol. 5:S10–S16. 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.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 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. Mick, D.L. 1974. Collaborative study of neurobehavioral and neurophysiological parameters in relation to occupational exposure to organophosphate pesticides. In: Behavioral Toxicology: Early Detection of Occupational Hazards. C. Xintaras, B.L. Johnson and I. de Groot, eds. Center for Disease Control, National Institute for Occupational Safety and Health, Washington, DC. pp. 152–153. Moeller, H.C. and J.A. Rider. 1962. Plasma and red blood cell cholinesterase activity as indications of the threshold of incipient toxicity of ethyl-p-nitrophenyl thiobenzenephosphorate (EPN) and malathion in human beings. Toxicol. Appl. Pharmacol. 4:123–130. (Cited in U.S. EPA, 1995a) Morgan, D.P. 1989. Recognition and Management of Pesticide Poisonings, 4th ed., EPA-540/9-88-001, U.S. Environmental Protection Agency, Washington, DC. Morrill, L.G., L.W. Reed and K.S.K. Chinn. 1985. Toxic Chemicals in the Soil Environment. Volume 2. Interaction of Some Toxic Chemicals/Chemical Warfare Agents and Soils. Oklahoma State University TECOM Project 2-CO-210-049, Stillwater, OK. Available from DTIC, AD-A158 215. Munro, N.B., K.R. Ambrose and A.P. Watson. 1994. Toxicity of the organophosphate chemical warfare agents GA, GB, and VX: Implications for public protection. Envir. Health Perspect. 102:18–38. O'Brien, R.D. 1960. Toxic Phosphorus Esters: Chemistry. Metabolism, and Biological Effects. Academic Press, New York NY, pp. 175–239. Rice, G.B., T.W. Lambert, B. Haas and V. Wallace. 1971. Effect of Chronic Ingestion of VX on Ovine Blood Cholinesterase. Technical Report DTC 71–512, Deseret Test Center, Dugway Proving Ground, Dugway UT. Rickett, D.J., J.F. Glenn and W.E. Houston. 1987. Medical defense against nerve agents: New directions. Mil. Med. 152:35–41. Rider, J.A., L.E. Ellinwood and J.M. Coon. 1952. Production of tolerance in the rat to octamethylpyrophosphoramide (OMPA). Proc. Soc. Exptl. Biol. Med. 81:455–459. Rodnitzky, R.L. 1974. Neurological and behavioral aspects of occupational exposure to organophosphate pesticides. In: Behavioral Toxicology: Early Detection of Occupational Hazards. C. Xintaras, B.L. Johnson and I. de Groot, eds. Center for Disease Control, National Institute for Occupational Safety and Health, Washington, DC. pp. 165–174. Rosenblatt, D.H., M.J. Small, T.A. Kimmell and A.W. Anderson. 1995. Agent Decontamination Chemistry Technical Report. U.S. Army Test and Evaluation Command (TECOM) Technical Report, Phase I. Draft Report, Argonne National Laboratory. RTECS (Registry of Toxic Effects of Chemical Substances). 1995. MEDLARS Online Information Retrieval System, National Library of Medicine, Computer printout. Sanches, M.L., C.R. Russell, and C.L. Randolf. 1993. Chemical Weapons Convention (CWC) Signature Analysis. DNA-TR-92-73, AD B171788, Defense Technical Information Center. Savage, E.P., T.J. Keefe, L.M. Mounce, et al. 1988. Chronic neurological sequelae of acute organophosphate pesticide poisoning. Arch. Environ. Health 43:38–45. Sidell, F.R. 1992. Clinical considerations in nerve agent intoxication. In: Chemical Warfare Agents, S. Somani, ed., Academic Press, N.Y., pp 155–194.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Sidell, F.R. and W.A. Groff. 1974. The reactivatibility of cholinesterase inhibited by VX and Sarin in man. Toxicol. Appl. Pharmacol. 27:241–252. Sidell, F.R. and A. Kaminskis. 1975. Temporal intrapersonal physiological variability of cholinesterase activity in human plasma and erythrocytes. Clin. Chem. 21:1961–1963. Singer, A.W., N.K. Jaax, J.S. Graham and C.G. McLeod, Jr. 1987. Cardiomyopathy in Soman and Sarin intoxicated rats. Toxicol. Letters 36:243–249. Small, M.J. 1984. Compounds Formed from the Chemical Decontamination of HD, GB, and VX and Their Environmental Fate. Technical Report 8304, AD A149515, US Army Medical Bioengineering Research and Development Laboratory, Fort Detrick, Frederick, MD. Somani, S.M., R.P. Solana and S.N. Dube. 1992. Toxicodynamics of nerve agents. In: Chemical Warfare Agents, S.M. Somani, ed., Academic Press, Inc. New York. pp. 67–123. Sumerford, W.T., W.J. Hayes, J.M. Johnston, K. Walker and J. Spillane. 1953. Cholinesterase response and symptomatology from exposure to organic phosphorus insecticides. AMA Arch. Ind Hyg. Occup. Med. 7:383–398. Tabershaw, I.R. and W.C. Cooper. 1966. Sequelae of acute organic phosphate poisoning. J. Occup. Med. 8:5–20. Tammelin, L.E. 1958. Organophosphorylcholines and cholinesterases. Arkiv. Kemi. 12(31):287–298. Thienes, C.H. and T.J. Haley. 1972. Clinical Toxicology. Lea and Febiger, Philadelphia, PA. pp. 95–115. U.S. EPA (U.S. Environmental Protection Agency). 1995a. Proposed Guidelines for Neurotoxicity Risk Assessment: Notice. Federal Register 60(192):52032–52056. U.S. EPA (U.S. Environmental Protection Agency). 1995b. Oral RfD Assessment for Malathion. Integrated Risk Information System (IRIS). Online file. Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH. U.S. EPA (U.S. Environmental Protection Agency). 1995c. Oral RfD Assessment for Ethion. Integrated Risk Information System (IRIS). Online file. Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH. U.S. EPA (U.S. Environmental Protection Agency). 1995d. Oral RfD Assessment for Aldicarb Sulfone. Integrated Risk Information System (IRIS). Online file. Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH. Wagner, S.L. 1983. Organophosphates. In: Clinical Toxicology of Agricultural Chemicals. Noyes Data Corporation, Park Ridge, NJ, pp. 205–246. Watson, A.P., K.R. Ambrose, G.D. Griffin, et al. 1989. Health effects of warfare agent exposure: implications for stockpile disposal. Environ. Prof. 11:335–353. Weimer, J.T., B.P. McNamara, E.J. Owens, et al. 1979. Proposed Revision of Limits for Human Exposure to GB Vapor in Nonmilitary Operations Based on One-Year Exposures of Laboratory Animals to Low Airborne Concentrations. ARCSL-TR-78056. U.S. Army Armament Research and Development Command, Chemical Systems Laboratory, Aberdeen Proving Ground MD. Wills, J.H. 1972. The measurement and significance of changes in the cholinesterase activities of erythrocytes and plasma in man and animals. CRC Crit. Rev. Toxicol. 1:153–202.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Windholz, M. S. Budavari, R.F. Blumetti and E.S. Otterbein, eds. 1983. The Merck Index. An Encyclopedia of Chemicals and Drugs. 10th ed. Merck and Co. Rahway, NJ. Yager, J., H. McLean, M. Hudes and R.C. Spear. 1976. Components of variability in blood cholinesterase assay results. J. Occup. Med. 18:242–244.

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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 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 ration 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 GB-Induced ChE Inhibition in Rats GB Type II - RBC Cholinesterase Inhibition in Female Ratsa (ANOVA and Dunnett's Comparison) Oral Dose (µg/kg/day) Week   -1 1 3 7 13 0   ns/ ns/ ns/ ns/ 75 _/ns ns/ns ns/ns ns/ns ns/ns 150 _/ns S/S S/ns S/S ns/S 300 _/ns S/S S/S S/S ns/S Source: Re-evaluation of data from Bucci and Parker, 1992. 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. GB Type II - RBC Cholinesterase Inhibition in Male Ratsa (ANOVA and Dunnett's Comparison) Oral Dose (µg/kg/day) Week   -1 1 3 7 13 0   ns/ ns/ ns/ ns/ 75 _/ns ns/ns ns/ns ns/ns ns/ns 150 _/ns S/S S/ns S/S ns/S 300 _/ns S/S S/S S/S ns/S Source: Re-evaluation of data from Bucci and Parker, 1992. 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 GB Type II - RBC Cholinesterase Inhibition in Female Ratsa (ANOVA and Dunnett's Comparison) Oral Dose (µg/kg/day) Week   -1 1 3 7 13 0   ns/ ns/ ns/ ns/ 75 _/ns ns/ns ns/ns ns/ns ns/ns 150 _/ns S/S S/ns S/S ns/S 300 _/ns S/S S/S S/S ns/S Source: Re-evaluation of data from Bucci and Parker, 1992. 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. GB Type II - RBC Cholinesterase Inhibition in Male Ratsa (ANOVA and Dunnett's Comparison) Oral Dose (µg/kg/day) Week   -1 1 3 7 13 0 0 ns/ ns/ ns/ ns/ 75 _/ns S/S S/S S/S ns/ns 150 _/ns S/S S/S S/S S/ns 300 _/ns S/S S/S S/S S/ns Source: Re-evaluation of data from Bucci and Parker, 1992. 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.