4
Evaluation of the Army's Interim Reference Dose for GB

THE CHEMICAL-WARFARE agent GB (also known as sarin) is an organophosphate nerve agent found at several stockpile and nonstockpile munition sites in the United States. At the request of the U.S. Army, Oak Ridge National Laboratory (ORNL) conducted a health risk assessment of GB. The assessment comprised a detailed analysis of GB's physical and chemical properties, environmental fate, mechanism of action, and animal and human toxicity data (see Appendix B, Health Risk Assessment of GB, ORNL 1996). On the basis of that assessment, ORNL proposed a reference doses (RfD) of 2 × 10-5 mg/kg of body weight per day for noncancer health effects of GB exposure. Because there was no evidence that GB is carcinogenic, a slope factor was not derived. The Army's Surgeon General accepted ORNL's proposed RfD as an interim exposure value until an independent evaluation of the proposed RfD was conducted by the National Research Council (NRC). This chapter contains the NRC's independent assessment of the scientific validity of the Army's interim RfD for GB.

DERIVATION OF THE ARMY'S INTERIM RFD

The Army's interim RfD for GB is 2 × 10-5 mg/kg per day. ORNL (1996) calculated that value on the basis of the lowest oral dose of GB that caused significant depression in red-blood-cell (RBC)-cholinesterase



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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 4 Evaluation of the Army's Interim Reference Dose for GB THE CHEMICAL-WARFARE agent GB (also known as sarin) is an organophosphate nerve agent found at several stockpile and nonstockpile munition sites in the United States. At the request of the U.S. Army, Oak Ridge National Laboratory (ORNL) conducted a health risk assessment of GB. The assessment comprised a detailed analysis of GB's physical and chemical properties, environmental fate, mechanism of action, and animal and human toxicity data (see Appendix B, Health Risk Assessment of GB, ORNL 1996). On the basis of that assessment, ORNL proposed a reference doses (RfD) of 2 × 10-5 mg/kg of body weight per day for noncancer health effects of GB exposure. Because there was no evidence that GB is carcinogenic, a slope factor was not derived. The Army's Surgeon General accepted ORNL's proposed RfD as an interim exposure value until an independent evaluation of the proposed RfD was conducted by the National Research Council (NRC). This chapter contains the NRC's independent assessment of the scientific validity of the Army's interim RfD for GB. DERIVATION OF THE ARMY'S INTERIM RFD The Army's interim RfD for GB is 2 × 10-5 mg/kg per day. ORNL (1996) calculated that value on the basis of the lowest oral dose of GB that caused significant depression in red-blood-cell (RBC)-cholinesterase

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents (ChE) activity in rats. The lowest-observed-adverse-effect level (LOAEL) of GB was 0.075 mg/kg per day in a subchronic toxicity study (Bucci and Parker 1992). In that study, male and female rats were administered GB by gavage for 5 days per week for 13 weeks. Because of the discontinuous exposure regimen, ORNL adjusted the LOAEL (LOAEL adj for continuous exposures by multiplying 0.075 mg/kg per day by a factor of 5/7 (i.e., 5 days/7 days) to yield a LOAELadj of 0.054 mg/kg per day. The RfD for GB was calculated to be 2 × 10-5 mg/kg per day by dividing the LOAELadj by 2,700, the product of the uncertainty factors and the modifying factor selected by ORNL. APPROPRIATENESS OF THE CRITICAL STUDY The critical study used by ORNL for deriving the RfD for GB was a subchronic toxicity study (Bucci and Parker 1992) in which Caesarian-derived Sprague-Dawley rats (12 males and 12 females per group) were administered GB with diisopropylcarbodiimide as a stabilizer (type II GB) by gavage at doses of 0.075, 0.15, and 0.3 mg/kg per day 5 days per week for 13 weeks. Plasma-ChE and RBC-acetylcholinesterase (AChE) measurements, as well as several other blood measurements, were taken before dosing and at the end of weeks 1, 3, 7, and 13. Plasma-ChE values in females of the mid-dose group were reported to be significantly lower than control values at weeks 1 and 7 and in the high-dose group at weeks 1, 3, and 7. In males, significant reduction in plasma ChE was observed in the low- and mid-dose groups only at week 1. ORNL reanalyzed the data using analysis of variance (ANOVA) and Dunnett's comparison and reported significant decreases in plasma ChE in females in the high-dose group at weeks 1, 3, and 7 and in the mid-dose group at weeks 1 and 3 compared with control and baseline values. A significant decrease was also observed in the mid-dose females at week 7 compared with control but not baseline values. For males, significant depression in plasma ChE was observed in the mid- and high-dose groups compared with control but baseline values. throughout the test period. At the low dose, significant decreases in ChE were observed at week 1 and 7 compared with control but not baseline values and at weeks 3 and 13 compared with baseline but not control values. Bucci and Parker (1992) reported significant dose-related RBC-AChE depression in female rats in the mid- and high-dose groups and in male

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents rats in all dose groups compared with controls. By week 13, the degree of inhibition was diminished, suggesting a compensatory increase in the hepatic synthesis of ChE to accommodate for the losses due to the repeated exposure and irreversible inhibition of AChE. ORNL reanalyzed the data using ANOVA and Dunnett's comparison and reported significantly lower RBC-AChE values in males in all dose groups compared with baseline values at weeks 1,3, and 7 and for the two highest dose groups at week 13. The values for all dose groups were also significantly lower than control values at weeks 1, 3, and 7. Similar results were observed with female rats in the mid- and high-dose groups, but RBC-AChE concentrations were not reduced significantly in the low-dose group compared with control or baseline values. Because there was a statistically significant reduction in RBC AChE in male rats at the lowest dose of 0.075 mg/kg per day, ORNL considered that dose to be the LOAEL for the study. The critical study (Bucci and Parker 1992) involved a relevant route of exposure (oral) for determining an RfD. Rats were administered GB by oral gavage, a route of administration that exaggerates the exposure that would normally occur from methods resulting in a slower rate of delivery (e.g., in feed or water). However, the study was subchronic in duration (13 weeks) rather than chronic (104 weeks), and ChE measurements varied and did not show a consistent dose-response relationship across ChE types and genders. Thus, the subcommittee believes that the study was too short in duration and that the results were too variable to form an ideal basis for determining a LOAEL. In addition, the methods used to measure ChE were not ideal (see Appendix G). However, in the absence of other well-conducted studies, the subcommittee agrees with ORNL that the study by Bucci and Parker (1992) is the most appropriate of the available studies for derivation of the RfD for GB. APPROPRIATENESS OF CRITICAL END POINT The LOAELadj (0.054 mg/kg per day) used by ORNL for derivation of the RfD for GB was based on the lowest dose that caused a significant depression in RBC AChE activity in rats (Bucci and Parker 1992). The subcommittee notes that ChE inhibition is typically considered a biomarker of exposure to organophosphate agents rather than an adverse effect. However, it is generally agreed that inhibition of ChE contributes

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents to the overall hazard identification of ChE-inhibiting agents. The U.S. Environmental Protection Agency (EPA) has used ChE inhibition to establish RfDs for several organophosphate pesticides, such as malathion (EPA 1992) and ethion (EPA 1989). The subcommittee considered other possible toxicity end points, notably neurotoxicity, associated with GB exposure. Organophosphate compounds like GB may act directly on nerve cell receptors or, by inhibiting neural AChE, interfere with neuromuscular transmission and produce delayed-onset subjunctional muscle damage. In addition, some organophosphate compounds cause a neurotoxic effect (organophosphate-induced delayed neuropathy, or OPIDN) that is not associated with ChE inhibition. OPIDN has not been observed in humans exposed to acutely toxic concentrations of GB (Munro et al. 1994), but some laboratory studies have suggested the OPIDN can be induced in mice (Husain et al. 1993) and chickens (Davies et al. 1960; Davies and Holland 1972; Gordon et al. 1983). However, other studies have shown conflicting results (Bucci et al. 1992). The subcommittee notes that ORNL did not consider all of the available human data on GB. In 1994, GB was released by terrorists in Matsumoto City, Japan, where approximately 600 residents and rescue staff were exposed to the agent (Morita et al. 1995). Since then, several studies on the effects of the exposure have been published (Murata et al. 1997; Nakajima et al. 1997, 1998; Yokoyama et al. 1998a,b). There have also been unconfirmed reports of persisting neurological effects following low-dose exposures to GB. Emerging research in those areas might indicate alternative end points to ChE inhibition that could be used to derive RfDs for nerve agents in the future. The subcommittee also notes that additional human data are available on anti-ChE agents, which were not included in ORNL's assessment. Data summaries from human experimentation conducted in the 1950s and 1960s were evaluated by the NRC in a series of reports titled Possible Long-Term Health Effects of Short-Term Exposure to Chemical Agents (NRC 1982, 1984, 1985). The reports include an evaluation of health records of volunteer soldiers who were exposed intravenously or intramuscularly to chemical-warfare agents, as well as a follow-up morbidity study conducted by the NRC in 1985. The NRC found no long-term health effects from short-term exposure to any specific chemical-warfare agent, but there was some evidence of an increase in malignant neoplasms among men exposed to anti-ChE agents. Although these studies are not

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents directly applicable to deriving RfDs, they add to the completeness of the data base on GB. Provided that appropriate assays were used, the subcommittee finds no reason at this time to alter the practice of using RBC-ChE or plasma-ChE inhibition as the critical end point and agrees with ORNL that such inhibition is the best available critical noncancer end point on which to base the calculation of the RfD for GB. APPROPRIATENESS OF UNCERTAINTY FACTORS For GB, ORNL assigned values greater than 1 to five uncertainty factors and a value of 1 to the modifying factor. The product of those factors was 2,700. The subcommittee evaluated each of the uncertainty factors and the modifying factor below. EXTRAPOLATION FROM ANIMAL TO HUMAN ORNL assigned a factor of 10 to the uncertainty factor for the extrapolation of data from animals to humans (UFA, citing evidence (Grob and Harvey 1958, Bucci and Parker 1992) that humans are more susceptible than rats to GB. Grob and Harvey (1958) reported that the single oral dose required to lower RBC AChE by 50% in humans was 0.01 mg/kg and that an average daily dose of 0.034 mg/kg for 3 days resulted in signs of moderate toxicity. In comparison, Bucci and Parker (1992) reported that GB administered to rats at a dose of 0.3 mg/kg per day for 90 days caused decreases in RBC-ChE concentrations but no signs of toxicity. Rats are known to have aliesterases (e.g., carbonyl esterase), which are enzymes in blood known to bind to and, therefore, reduce the toxicity of GB (Fonnum and Sterri 1981). Aliesterases are not present in humans (Cohen et al. 1971). The subcommittee also notes that rats have true ChE (AChE) in their plasma (Traina and Serpietri 1984), a factor that might reduce the toxicity of GB in rats. ORNL also presented a comparison of acute toxicity values for GB (see Appendix B, Table 2). The data suggest that humans are more susceptible than rats to GB; however, such an evaluation is weakened by the fact that it is based on data from secondary references (i.e., RTECS 1995) and the human estimates are based on animal data (i.e., Somani et al. 1992). The subcommittee suggests that the original data cited in the

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents secondary reference be verified and the primary reference cited appropriately. Given the available data on GB, the subcommittee agrees with ORNL that a factor of 10 is appropriate for interspecies extrapolation. The factor of 10 should be considered an estimate of the difference in sensitivity between humans and rats to GB and not a default value. PROTECTING SUSCEPTIBLE SUBPOPULATIONS ORNL used a factor of 10 for the uncertainty factor to protect susceptible subpopulations (UFH because some individuals have a genetic polymorphism causing their serum-ChE 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 value (Bonderman and Bonderman 1971). Genetic polymorphisms are also recognized for butyrylcholinesterase and paraoxonase, enzymes that might function in the sequestration and metabolism of organophosphate nerve agents (Loewenstein-Lichtenstein et al. 1995; Maekawa et al. 1997; Furlong et al. 1998). Individuals with those polymorphisms might be unusually susceptible to organophosphate anti-ChE compounds (Morgan 1989). The subcommittee agrees with ORNL that a factor of 10 is appropriate for protecting this susceptible subpopulation. EXTRAPOLATION FROM LOAEL TO NOAEL ORNL assigned a factor of 3 rather than 10 to the uncertainty factor for extrapolation from a LOAEL to a NOAEL (UFL) because ChE inhibition is a biomarker of exposure rather than a toxic effect. Although it could be argued that a dose of GB that significantly induces ChE inhibition in the absence of toxic effects is indicative of a NOAEL rather than a LOAEL, the subcommittee agrees that a factor of 3 is a conservative choice for UFL. EXTRAPOLATION FROM SUBCHRONIC TO CHRONIC EXPOSURES In the derivation of RfDs for other organophosphate compounds, ORNL noted that EPA (1989, 1992) used NOAELs for ChE inhibition that were

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents based on subchronic exposure data without adjustment for chronic exposures, because ChE inhibition is unlikely to change over time. Hence, a factor of 1 was used for the uncertainty factor for extrapolation from subchronic to chronic exposures (UFS). For example, studies with the nerve agent VX indicate that maximal ChE inhibition occurs after 30–60 days of exposure and then levels off and sometimes shows signs of recovery (Goldman et al. 1988). However, because chronic exposure studies are not available to verify that additional effects would not occur from longer exposures to GB, ORNL assigned a factor of 3 to UFS. The subcommittee agrees that a factor of 3 is appropriate. DATA-BASE ADEQUACY As noted by ORNL, the most significant deficiency in the data base on GB is a multigeneration reproductive study. However, because two developmental toxicity studies on GB (Denk 1975; La Borde and Bates 1986) and a multigeneration reproductive study on VX (Goldman et al. 1988) indicate that reproductive effects are unlikely, the subcommittee agrees with ORNL that a factor of 3 for the uncertainty factor for data-base adequacy (UFD) is appropriate. MODIFYING FACTOR FOR ADDITIONAL UNCERTAINTY The subcommittee considers the uncertainties of the data on GB to be represented adequately by the values assigned to the uncertainty factors above and agrees with ORNL that a modifying factor (MF) of 1 is appropriate. SUMMARY Table 4-1 presents the values assigned to the uncertainty factors and the modifying factor used by ORNL and those recommended by the subcommittee. The subcommittee's recommendations are the same as those of ORNL.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents TABLE 4-1 Uncertainty Factors Used by ORNL and the NRC to Calculate the RfD for GB Uncertainty Factor Description ORNL NRC UFA For animal-to-human extrapolation 10 10 UFH To protect susceptible subpopulations 10 10 UFL For LOAEL-to-NOAEL extrapolation 3 3 UFS For subchronic-to-chronic extrapolation 3 3 UFD For data-base adequacy 3 3 MF Modifying factor for additional uncertainty 1 1 TOTAL UF   2,700 2,700 Abbreviations: LOAEL, lowest-observed-adverse-effect level; MF, modifying factor; NOAEL, no-observed-adverse-effect level; NRC, National Research Council; ORNL, Oak Ridge National Laboratory; RfD, reference dose; UF, uncertainty factor WEIGHT AND STRENGTH OF EVIDENCE The subcommittee believes that the strength of evidence for the Army's interim RfD of 2 × 10-5 mg/kg per day for GB is moderately good. There is a possibility that the LOAEL (0.075 mg/kg per day) used to calculate the RfD for GB is not accurate, because lower doses were not tested and variability in the RBC-ChE values was considerable. The subcommittee believes that because ChE inhibition is a biomarker of exposure rather than a toxic effect, use of this end point overestimates the oral toxicity of GB. CONCLUSIONS The approach used by ORNL to calculate the RfD for GB is consistent with the guidelines of the EPA. On the basis of available toxicity and related data on GB, the subcommittee concludes that the Army's interim RfD for GB of 2 × 10-5 mg/kg per day is scientifically valid.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents DATA GAPS AND RESEARCH RECOMMENDATIONS The major gap in the available information on GB is the lack of an oral subchronic or chronic toxicity study that demonstrates a clear LOAEL or NOAEL. The absence of that type of data could be addressed by conducting a subchronic oral toxicity study that assesses anti-ChE activity in RBCs and plasma in one or preferably two species. At least one dose between 0 and 0.075 mg/kg per day should be used. If further research reveals that significant toxic effects can be induced by any of the nerve agents evaluated (i.e., GA, GB, GD, or VX) at doses below those that cause significant ChE inhibition, new studies should be conducted reassess the safety of the recommended RfD for GB. REFERENCES Bonderman, R.P., and D.P. Bonderman. 1971. Atypical and inhibited human serum pseudocholinesterase. A titrimetric method for differentiation. Arch. Environ. Health 22:578–581. 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. FDA 224-85-0007. DTIC AD-A248618. Prepared by the Center for Toxicological Research, Jefferson, Ark., for the U.S. Army Biomedical Research and Development Laboratory, Fort Detrick, Frederick, Md. Bucci, T.J., R.M. Parker, and P.A. Gosnell. 1992. Toxicity Studies on Agents GB and GD (Phase II): Delayed Neuropathy Study of Sarin, Type II, in SPF White Leghorn Chickens. Technical Report. NCTR-TR-478,479. DTICAD-A257357. Prepared by the National Center for Toxicological Research, Jefferson, Ark., for U.S. Army Biomedical Research and Development Laboratory, Fort Detrick, Frederick, Md. Cohen, E.M., P.J. Christen, and E. Mobach. 1971. The Inactivation of Oximes of Sarin and Soman in Plasma from Various Species. I. The Influence of Diacetylmonoxime on the Hydrolysis of Sarin. Pp. 113–131 in Proceedings of the Koninklijke Nederlandse Akademie Van Wetenschappen, Series C, Biological and Medical Sciences, Vol. 74. J.A. Cohen Memorial issue. Amsterdam: North-Holland. Davies, D.R., P. Holland, and M.J. Rumens. 1960. The relationship between the chemical structure and neurotoxicity of alkyl organophosphorus compounds. Br. 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.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Denk, J.R. 1975. Effects of GB on Mammalian Germ Cells and Reproductive Parameters. EB-TR-74087. AD-A006503. Edgewood Arsenal, Aberdeen Proving Ground, Edgewood, Md. EPA (U.S. Environmental Protection Agency). 1989. Ethion Reference Dose for Chronic Oral Exposure. Integrated Risk Information System (IRIS). Online file. http://www.epa.gov/iris/ (Accessed July 22, 1998). EPA (U.S. Environmental Protection Agency). 1992. Malathion Reference Dose for Chronic Oral Exposure. Integrated Risk Information System (IRIS). Online file. http://www.epa.gov/iris/ (Accessed July 22, 1998). Evans, F.T., P.W.S. Gray, H. Lehmann, and E. Silk. 1952. Sensitivity to succinylcholine in relation to serum cholinesterase. Lancet i: 1129–1230. Fonnum, F., and S.H. Sterri. 1981. Factors modifying the toxicity of organophosphorus compounds including soman and sarin. Fundam. Appl. Toxicol. 1:143–147. Furlong, C.D., W.F. Li, L.G. Costa, R.J. Richter, D.M. Shih, and A.J. Lusis. 1998. Genetically determined susceptibility to organophosphorus insecticides and nerve agents: Developing a mouse model for the human PON1 polymorphism. Neurotoxicology 19:645–650. 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. DTIC AD-A201397. Prepared by the Laboratory for Energy Related Health Research, University of California, Davis, Calif., for the U.S. Army Medical Research and Development Command, Fort Detrick, Frederick, Md. Grob, D., and J.C. Harvey. 1958. Effects in man of the anticholinesterase compound Sarin (isopropyl methyl phosphonofluoridate). J. Clin. Invest. 37:350–368. Gordon, J.J., R.H. Inns, M.K. Johnson, L. Leadbeater, M.P. Maidment, D.G. Upshall, G.H. Cooper, and R.L. Rickard. 1983. The delayed neuropathic effects of nerve agents and some other organophosphorus compounds. Arch. Toxicol. 52:71–82. Harris, H., and M. Whittaker. 1962. The serum cholinesterase variants. A study of twenty-two families selected via the ''intermediate" phenotype. Ann. Hum. Genet. 26:59–72. Husain, K.R., R. Vijayaraghavan, S.C. Pant, S.K. Raza, and K.S. Pandey. 1993. Delayed neurotoxic effect of sarin in mice after repeated inhalation exposure. J. Appl. Toxicol. 13:143–145. La Borde, 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. Prepared by the National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Ar., for the U.S. Army Medical Research and Development Command, Fort Detrick, Md. Lowenstein-Lichtenstein, Y., M. Schwarz, D. Glick, B. Norgaard-Pederson, H. Zakut, and H. Soreq. 1995. Genetic predisposition to adverse consequences

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents of anti-cholinesterases in "atypical" BCHE carriers. Nat. Med. 1:1082–1085. Maekawa, M., K. Sudo, D.C. Dey, J. Ishikawa, M. Izumi, K. Kotani, and T. Kanno. 1997. Genetic mutations of butyrylcholine esterase identified from phenotypic abnormalities in Japan. Clin. Chem. 43:924–929. Morgan, D.P. 1989. Recognition and Management of Pesticide Poisonings, 4th Ed. EPA-540/9-88-001. U.S. Environmental Protection Agency, Health Effects Division, Office of Pesticide Programs, Washington, D.C. Morita, H., N. Yanagisawa, T. Nakajima, M. Shimizu, H. Hirabayashi, H. Okudera, M. Nohara, Y. Midorikawa, and S. Mimura. 1995. Sarin poisoning in Matsumoto, Japan. Lancet 346 (8970): 290–293. 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. Environ. Health Perspect. 102:18–38. Murata, K., S. Araki, K. Yokoyama, T. Okumura, S. Ishimatsu, N. Takasu, and R.F. White. 1997. Asymptomatic sequelae to acute sarin poisoning in the central and autonomic nervous system 6 months after the Tokyo subway attack. J. Neurol. 244:601–606. Nakajima, T., S. Sato, H. Morita, and N. Yanagisawa. 1997. Sarin poisoning of a rescue team in the Matsumoto sarin incident in Japan. Occup. Environ. Med. 54:697–701. Nakajima, T., S. Ohta, H. Morita, Y. Midorikawa, S. Mimura, and N. Yanagisawa. 1998. Epidemiological study of sarin poisoning in Matsumoto City, Japan. J. Epidemiol. 8:33–41. NRC (National Research Council). 1982. Possible Long-Term Health Effects of Short-Term Exposure to Chemical Agents, Vol. 1. Anticholinesterases and Anticholinergics. Washington, D.C.: National Academy Press. NRC (National Research Council). 1984. Possible Long-Term Health Effects of Short-Term Exposure to Chemical Agents, Vol. 2. Cholinesterase Reactivators, Psychochemicals, and Irritants and Vesicants. Washington, D.C.: National Academy Press. NRC (National Research Council). 1985. Possible Long-Term Health Effects of Short-Term Exposure to Chemical Agents, Vol. 3. Final Report. Current Health Status of Test Subjects. Washington, D.C.: National Academy Press. ORNL (Oak Ridge National Laboratory). 1996. Health Risk Assessment for the Nerve Agent GB. Draft Report. Interagency Agreement No. 1769-1769-A1. Prepared by Oak Ridge National Laboratory, Life Sciences Division, Oak Ridge, Tenn., for the U.S. Department of the Army, Army Environmental Center, Aberdeen Proving Ground, Edgewood, Md. RTECS (Registry of Toxic Effects of Chemical Substances). 1995. MEDLARS Online Information Retrieval System, National Library of Medicine, Bethesda, Md. Somani, S.M., ed. 1992. Chemical Warfare Agents. San Diego, Calif.: Academic.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Traina, M.E., and L.A. Serpietri. 1984. Changes in the levels and forms of rat plasma cholinesterases during chronic diisopropylphosphorofluoridate intoxication. Biochem. Pharmacol. 33:645–653. Yokoyama, K., S. Araki, K. Murata, M. Nishikitani, T. Okumura, S. Ishimatsu, N. Takasu, and R.F. White. 1998a. Chronic neurobehavioral effects of Tokyo subway sarin poisoning in relation to posttraumatic stress disorder. Arch. Environ. Health 53:249–256 Yokoyama, K., S. Araki, K. Murata, M. Nishikitani, T. Okumura, S. Ishimatsu, and N. Takasu. 1998b. Chronic neurobehavioral and central and autonomic nervous system effects of Tokyo subway sarin poisoning. J. Physiol. (Paris) 92:317–323.