APPENDIX D
Health Risk Assessment for The Nerve Agent VX



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

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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 VX 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 VX (CAS No. 50782-69-9). 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   4     2.2.1 Intra- and Interspecies Variation in Blood Cholinesterase Activity   4     2.2.2 Potency of Nerve Agents as Cholinesterase Inhibitors   6     2.2.3 Cholinesterase Inhibition by VX   6     3. Toxicology   7     3.1 Introduction   7     3.2 Acute Toxicity   7     3.3 Subchronic Toxicity   9     3.4 Chronic Toxicity   10     3.5 Nervous System Toxicity   11     3.6 Developmental and Reproductive Effects   12     3.7 Carcinogenicity   13     3.8 Genotoxicity   13     4. Oral Reference Dose for VX   14     4.1 Cholinesterase Inhibition as an RfD Endpoint   14     4.2 Derivation of the Oral RfD   15     4.3 Overall Confidence in the Oral RfD   18     4.4 Comparison of the RfD with Human Toxicity Data   19     5. Carcinogenicity Assessment   19     6. References Cited   20     Appendix A. Comparison of RfDs, ChE Inhibition and Toxicity Data for GA, GB, GD and VX   A-1     Appendix B. Graphical Analysis of Rice et al. (1971) Data for Sheep Dosed with VX   B-1     Appendix C. Statistical Analysis of RBC-AChE Inhibition in Rats Dosed with VX   C-1     Appendix D. Oral RfD Estimated from Human Data   D-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.   RBC-ChE activity in sheep fed VX   9 Table 3.   RBC-ChE activity in rats injected subcutaneously with VX   11 Table 4.   Regression analysis of Rice et al. (1971) data for sheep dosed with VX   19 Table 5.   Comparison of RfD with human toxicity data for VX   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). VX contains a sulfur substituent group (for comparison GB contains fluorine and GA contains a cyanide group). The chemical synonyms, Chemical Abstract Service (CAS), Army identification numbers (DA, 1974, 1992; Dacre, 1984), and chemical formula for VX are as follows: Phosphonothioic acid, methyl-, S-[2-[bis(1-methylethylamino)ethyl] O-ethyl ester; Phosphonothioic acid, methyl, S-(2-(diisopropylamino)ethyl) O-ethyl ester; O-Ethyl S-(2-diisopropylaminoethyl) methylphosphonothiolate; S-2-Diisopropylaminoethyl O-ethyl methylphosphonothiolate; O-Ethyl S-(2-diisopropylaminoethyl) methylthiolphosphonate; TX60; CAS No. 50782-69-9; Edgewood Arsenal No. 1701 1.1. PHYSICAL/CHEMICAL PROPERTIES Agent VX is a colorless to straw-colored liquid with a molecular weight of 267.4 (DA, 1974, MacNaughton and Brewer, 1994); it has a vapor density of 9.2 (air = 1) and a liquid density of 1.0083 g/ml at 25°C (DA, 1974). The vapor pressure of VX is 0.0007 mm Hg at 25°C; its water solubility is 30 g/L per 100 g at 25°C and 7.5 g per 100 g at 15°C (DA, 1974). 1.2. ENVIRONMENTAL FATE 1.2.1 Air The volatility of agent VX is relatively low (vapor pressure 0.0007 mm HG (DA, 1974; MacNaughton and Brewer, 1994). A vapor concentration of 10.5 mg/m3 has been reported for a temperature of 25°C (DA, 1974) (although not adequately described in the reference, this is presumably the saturation concentration above a pure liquid). Because VX does not absorb UV radiation above 290 nm (Rewick et al., 1986), photodegradation is not a significant environmental fate process. Based on structure-activity relationships, VX is predicted to react in the troposphere with photochemically produced hydroxyl radicals, with a half-life estimated to be 0.24 days (Atkinson, 1987).

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 1.2.2 Water VX has a water solubility of 3 g per 100 g solvent at 25°C and 7.5 g per 100 g solvent at 15°C (DA, 1974). It's Henry's Law Constant has been estimated to be 3.5×10-9 atm m3/mol, indicating a low potential for evaporation from water (MacNaughton and Brewer, 1994); its evaporation rate is about 1/1,500 that of water (Rosenblatt et al., 1995). The agent is relatively resistant to hydrolysis (Franke, 1982); reported half-lives in water at 25°C and pH 7 range from 400 to 1000 hours (Clark, 1989); half-life increases under acidic conditions [(100 days at pH 2–3 (DA, 1974)]. Although solubility is increased at lower temperatures, low temperatures decrease the rate of hydrolysis (Clark, 1989). VX in surface waters may sink and be adsorbed by sediment (Trapp, 1985). 1.2.3 Soil VX is moderately persistent on bare ground and may remain in significant concentrations for varying time periods, depending on temperature, organic carbon content of the soil, and moisture (Sage and Howard, 1989). Its volatility potential (slope of the vapor pressure vs. concentration in soil organics) of 3.0×10-11 mm Hg/mg/kg and its air-soil partition coefficient (for a soil density of 1.4 g/cm3) of 1.5×10-8 mg/m3 (MacNaughton and Brewer, 1994), indicate that relatively little will evaporate into air. In the laboratory, unstabilized VX of 95% purity decomposed at a rate of 5% per month at 22°C (DA, 1992). In contrast, VX in soils from Carroll Island, MD (a chemical agent test site) decreased to 2.5–7.2% of initial levels (10 mg/g soil) after 14 days storage at room temperature in closed containers (studies reviewed by Small, 1984). In similar studies conducted with soil from Dugway Proving Ground, VX levels (initially 1 mg/g of soil) decreased 79% after 3 days and 90% after 15 days. In other laboratory studies, a VX concentration of 0.2 mg/g in humic sand decreased by 78% after one day, and the same concentration in humic loam and clayey peat decreased by 98% in one day; only 0.1% of the applied amount was detected after 3 weeks in either soil type (Kaaijk and Frijlink, 1977; Verweij and Boter, 1976). Degradation of VX in soil has also been evaluated in several field studies (see review by Small, 1984). At Carroll Island, MD, VX sprayed on soil decreased by about three orders of magnitude within 17 to 52 days. In an area of Dugway Proving Ground, where VX soil levels prior to 1969 were as high as 6 mg/g, no VX was detected (detection limit 0.4 µg/g) 10 years later. The degradation product, methyl phosphonic acid, was detected at concentrations ranging from 14.9 to 23 µg/g. Approximately three weeks after an accidental release of VX near the Dugway Proving Ground snow samples contained 7–9 ng VX per 400–500 gm of water and grass samples contained 4 µg VX per 900 gm of solid material [estimates based on an assumed 100% extraction efficiency (Sass et al., 1970)]. 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),

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 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 Compounds 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 chemical agents, these compounds can apparently affect nerve-impulse transmission by more direct processes as well. In addition to cholinesterase inhibition, VX reacts directly with ACh receptors and receptors of other neurotransmitters (e.g., norepinephrine, dopamine, gamma-aminobutyric acid) (Zhao et al., 1983; Ho and Hoskins, 1983; Chen and Chi, 1986; Idriss et al., 1986). 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; however, nanomolar blood concentrations of 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.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 2.2 Effect on Blood Cholinesterases Acetylcholinesterase is a natural component of human blood, where it is found on the surface of red blood cells (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 have been used as bioindicators of potential toxic effects of organophosphate cholinesterase inhibitors. 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 × 10-9 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 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-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 preexposure values without any other signs or symptoms of exposure. 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 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, 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 with 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 more acutely toxic than agents GA, GB, or GD (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-ChE 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

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents DA (U.S. Department of the Army). 1992. Material Safety Data Sheets: HD and THD. 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 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. Franke, S. 1982. Textbook of Military Chemistry, Volume 1. USAMIIA-HT-039-82, AD B062913, Defense Technical Information Center. 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. 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. 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.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 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 Studies in Man. William and Wilkins, Baltimore, MD. Ho, I.K. and B. Hoskins. 1983. Basal Ganglia Dopamine-Gamma Aminobutyric Acid-Acetylcholine Interaction in Organophosphate-Induced Neurotoxicity. Second Annual Report. AD B091748. U.S. Army Medical Research and Development Command, Fort Detrick, Frederick, MD. 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. Idriss, M.K., L.G. Aguayo, D.L. Rickett, and E.X. Albuquerque. 1986. Organophosphate and carbamate compounds have pre- and postjunctional effects at the insect glutamatergic synapse. J. Pharmacol. Exp. Ther. 239:279–285. Ivanov, P., B. Georgiev, K. Kirov and L. Venkov. 1993. Correlation between concentration of cholinesterase and the resistance of animals to organophosphorus compounds. Drug and 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. Kaaijk, J. and C. Frijlink. 1977. Degradation of S-2-diisopropylaminoethyl O-ethyl methylphonothioate in soil: sulfur-containing products. Pestic. Sci. 8:510–514. Kimura, K.K., B.P. McNamara, and V.M. Sim. 1960. Intravenous Administration of VX in Man. Technical Report CRDLR 3017. U.S. Army, Chemical Corps Research and Development Command, Chemical Research and Development Laboratories, Army Chemical Center, MD. 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., F. Leitnaker and F.J. Vocci. 1973. Proposed Limits for Human Exposure to VX Vapor in Nonmilitary Operations. EASP 1100-1 (R-1), AD 770434/9. 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 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. Morgan, D.P. 1989. Recognition and Management of Pesticide Poisonings, 4th ed., EPA-540/9-88-001, U.S. Environmental Protection Agency, Washington, DC. 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. Olajos, E.J., J. Bergmann, J.T. Weimer, and H. Wall. 1986. Neurotoxicity assessment of O-ethyl-O'-(2-diisopropylaminoethyl)methylphosphonite (QL) in hens. J. Appl. Toxicol. 6:135–143. Osweiler, G.D., T.L. Carson, W.B. Buck and G.A. Van Gelder. 1985. Clinical and Diagnostic Veterinary Toxicology, 3rd ed. Kendall/Hunt Publ. Co., Dubuque, Iowa. Rewick, R.T., M.L. Shumacher and D.L. Haynes. 1986. The UV absorption spectra of chemical agents and simulants. Appl. Spectroscopy 40:152–156. 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, W.E. Houston. 1987. Medical defense against nerve agents: New directions. Mil. Med. 152:35–41. (Cited in Munro et al., 1994) 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). National Institute for Occupational Safety and Health, online file retrieved December, 1995. Sage, G.W. and P.H. Howard. 1989. Environmental Fate Assessments of Chemical Agents HD and VX. CRDECCR-034, Aberdeen Proving Ground, MD. Sass, S., T.L. Fisher, M.H. Stutz and R.J. Piffath. 1970. Analysis of Environmental Samples from Area of Sheep Deaths near Dugway Proving Ground (U). EASP 100-69, Department of the Army, Edgewood Arsenal, MD.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 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. Schreider, J.P, J.R. Rowland, L.S. Rosenblatt and A.G. Hendrick. 1984. The Teratologic Effects of VX in Rats. Draft Final Report. Laboratory for Energy-Related Health Effects Research. University of California, Davis, CA. Prepared for U.S. Army Medical Bioengineering Research and Development Laboratory, Fort Detrick, MD. (Cited in Carnes et al., 1986) Sidell, F.R. 1992. Clinical considerations in nerve agent intoxication. In: Chemical Warfare Agents, S. Somani, ed., Academic Press, N.Y., pp. 155–194. 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, Sim, V.M. 1962. Variability of Different Intact Human Skin Sites to the Penetration of VX. Technical Report CRDLR 3122. U.S. Army Chemical Corps Research and Development Command, Chemical Research and Development Laboratories, Army Medical Center, MD. Sim, V.M. and J.L. Stubbs. 1960. Percutaneous Studies in Man. Technical Report CRDLR 3015, AD 318533. U.S. Army Chemical Research and Development Laboratories, Army Chemical Center, MD. Sim, V.M., C. McClure, Jr., F.J. Vocci, L. Feinsilver, and W.A. Groff. 1964. Tolerance of Man to VX-Contaminated Water. Technical Report CRDLR 3231. U.S. Army Chemical Research and Development Laboratories, Edgewood Arsenal, MD. 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. Thienes, C.H. and T.J. Haley. 1972. Clinical Toxicology. Lea and Febiger, Philadelphia, PA. Trapp, R. 1985. The Detoxification and Natural Degradation of Chemical Warfare Agents. Taylor and Francis, London. U.S. EPA (U.S. Environmental Protection Agency). 1995a. Proposed Guidelines for Neurotoxicity Risk Assessment: Notice. Federal Register 60(192):52032-52056.

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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.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents APPENDIX B Graphical Analysis of Rice et al. (1971) Data for Sheep Dosed with VX

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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 RBC-AChE Inhibition in Male Rats Dosed With VX Study: Goldman et al., 1988 Species/sex: Sprague-Dawley rats/males Endpoint: RBC-cholinesterase inhibition Analysis: Comparisons made with controls (0 µ/kg/day) at 30 days Dose (µ/kg) 0 0.25 1.0 4.0       Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Mean 3.36 1.546 0.74 0.13     Std 0 0.06 0.0007 0.003     N 2 2 2 2     Bartlett's Test for homogeniety indicates the data is suitable for ANOVA. ANOVA SS Between 11.807 df = 3   F = 4361.593 SS Among 0.004 df = 4   p = <0.001 MS Among 3.936           MS Between 0.001           Scheffe's Comparison Comparison with:   Group 2 Group 3 Group 4     Group 1   p<0.05 p<0.05 p<0.05     Group 2     p<0.05 p<0.05     Group 3       p<0.05     Dunnett's Comparison Comparison with:   Group 2 Group 3 Group 4     Group 1   p<0.05 p<0.05 p<0.05     Group 2     p<0.05 p<0.05     Group 3       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 RBC-AChE Inhibition in Female Rats Dosed With VX Study: Goldman et al., 1988 Species/sex: Sprague-Dawley rats/females Endpoint: RBC-cholinesterase inhibition Analysis: Comparisons made with controls (0 µg/kg/day) at 30 days Dose (µg/kg) 0 0.25 1.0 4.0       Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Mean 2.86 1.37 0.57 0.29     Std 0 0.08 0.006 0.014     N 2 2 2 2     Bartlett's Test for homogeniety indicates the data is suitable for ANOVA. ANOVA SS Between 7.977 df = 3   F = 1603.729 SS Among 0.007 df = 4   p = <0.001 MS Among 2.659           MS Between 0.002           Scheffe's Comparison Comparison with: Group 2 Group 3 Group 4       Group 1 p<0.05 p<0.05 p<0.05       Group 2   p<0.05 p<0.05       Group 3     p<0.05       Dunnett's Comparison Comparison with: Group 2 Group 3 Group 4       Group 1 p<0.05 p<0.05 p<0.05       Group 2   p<0.05 p<0.05       Group 3     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 D CALCULATION OF ORAL RFD FROM HUMAN DATA Study: Sim et al., 1964 Dose: 1.43 µg/kg/day orally for 7 days Effect: 60% RBC-ChE inhibition but no toxic effects LOAEL: 1.43 µg/kg/day Reference Dose: where: UF1 = 10 (sensitive subpopulations). UF2 = 1 (animal to human extrapolation), not needed. UF3 = 3 (extrapolation from 7-day exposure to subchronic exposures). Animal data suggest that ChE effects may increase over the first 30–60 days of exposure and then follow a slow rate of recovery. UF4 = 10 (LOAEL to a NOAEL extrapolation); 60% inhibition is near a level where physical signs of clinical toxicity may occur. UF5 = 1 the data base requirements are met and cholinesterase inhibition is considered to be the mechanism of toxicity. MF = 1 no modifying factor is needed. therefore:

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