3
Evaluation of the Army's Interim Reference Dose for GA

THE CHEMICAL-WARFARE agent GA (also known as tabun) is an organophosphate nerve agent found at several stockpile and nonstockpile munition sites in the United States and its territories. At the request of the U.S. Army, Oak Ridge National Laboratory (ORNL) conducted a health risk assessment of GA. The assessment included a detailed analysis of GA's physical and chemical properties, environmental fate, mechanism of action, and animal and human toxicity data (see Appendix A, Health Risk Assessment of GA, ORNL 1996). On the basis of that assessment, ORNL proposed a reference dose (RfD) of 4× 10-5 mg/kg of body weight per day for noncancer health effects of GA exposure. Because there was no evidence that GA 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 GA.

DERIVATION OF THE ARMY'S INTERIM RFD

The Army's interim RfD for GA is 4 × 10-5 mg/kg per day (or 0.04 µg/kg per day). ORNL (1996) calculated that value on the basis of the highest intraperitoneal (i.p.) dose of GA that did not cause significant



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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 3 Evaluation of the Army's Interim Reference Dose for GA THE CHEMICAL-WARFARE agent GA (also known as tabun) is an organophosphate nerve agent found at several stockpile and nonstockpile munition sites in the United States and its territories. At the request of the U.S. Army, Oak Ridge National Laboratory (ORNL) conducted a health risk assessment of GA. The assessment included a detailed analysis of GA's physical and chemical properties, environmental fate, mechanism of action, and animal and human toxicity data (see Appendix A, Health Risk Assessment of GA, ORNL 1996). On the basis of that assessment, ORNL proposed a reference dose (RfD) of 4× 10-5 mg/kg of body weight per day for noncancer health effects of GA exposure. Because there was no evidence that GA 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 GA. DERIVATION OF THE ARMY'S INTERIM RFD The Army's interim RfD for GA is 4 × 10-5 mg/kg per day (or 0.04 µg/kg per day). ORNL (1996) calculated that value on the basis of the highest intraperitoneal (i.p.) dose of GA that did not cause significant

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents depression in plasma cholinesterase (ChE) activity in rats. The no-observed-adverse-effect level (NOAEL) of GA was 28.13 µg/kg per day in a subchronic toxicity study (Bucci et al. 1992). In that study, male and female rats were injected i.p. with GA 5 days a week for 13 weeks. To estimate the equivalent oral NOAEL from the i.p. NOAEL, ORNL compared the oral and i.p. LD50 (lethal dose to 50% of test animals) values for the rat and assumed that the same ratio would apply for longer-term exposures. Rat studies reported an oral LD50 of 3,700 µg/kg (RTECS 1995) and i.p. LD50 of 490 µg/kg (RTECS 1995) and 800 µg/kg (U.S. Department of the Army 1974) (average 645 µg/kg). Thus, the equivalent oral NOAEL was calculated as follows: Because of the discontinuous exposure regimen, ORNL adjusted the equivalent oral NOAELadj for continuous exposures by multiplying 161 µg/kg per day by a factor of 5/7 (i.e., 5 days/7days) to yield a NOAELadj of 115 µg/kg per day (or 0.115 mg/kg per day). The RfD for GA was calculated to be 4 × 10-5 mg/kg per day by dividing the NOAELadj 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 GA was a subchronic toxicity study (Bucci et al. 1992) in which Caesarian-derived Sprague-Dawley rats (12 males and 12 females per group) were injected i.p. with GA at doses of 28.13, 56.25, and 112.50 µg/kg per day for 5 days per week for 13 weeks and then sacrificed and necropsied. PlasmaChE and red-blood-cell (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. Considerable variability was observed in RBC-AChE concentrations. Significant depression in RBC AChE was observed in female rats in the mid-and high-dose groups at weeks 7 and 3, respectively, compared with control values and in male rats at all doses at week 1. Bucci et al. (1992) reported that mean baseline values (measurements taken before exposure) for RBC AChE

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents were substantially increased in male and female rats compared with control values recorded in previous nerve-agent studies conducted in the same laboratory. The increased baseline values were attributed to faulty reagents. The percentage reduction caused by exposure to GA was noted to be in the same range as in the earlier work. ORNL (1996) reanalyzed the data with analysis of variance (ANOVA) and Dunnett's comparison and reported significant depression in RBC AChE in females at all doses at weeks 1 and 7 and at the high dose at week 3 compared with baseline values but not compared with control values. For male rats, RBC-AChE concentrations were significantly reduced in the low- and mid-dose groups compared with baseline values but not with control values. Plasma-ChE measurements were reported by Bucci et al. (1992) to be significantly decreased in females of the mid- and high-dose groups before exposure and at weeks 1,3, and 7 compared with controls but not at week 13. In males, significant decreases in plasma ChE were observed in the high-dose group at weeks 3 and 7. ORNL (1996) reanalyzed the data with ANOVA and Dunnett's comparison and reported a significant decrease in plasma ChE in females at all doses at weeks 1, 3, and 7 compared with control values but not with baseline values. At week 13, a significant increase in plasma ChE was observed in females in the low-dose group. This increase might be due to the compensatory increase in the synthesis of ChE to accommodate the losses due to the repeated exposure and irreversible inhibition AChE. For males, significant decreases in plasma ChE were observed in the mid- and high-dose groups at weeks 1, 3, and 7 compared with control and baseline values; in addition, significant decreases were observed in the mid-dose group at weeks 1 and 13 compared with baseline but not controls values. ORNL noted that plasma-ChE values in male rats provided the least variable indicator of the lowest-observed-adverse-effect level (LOAEL) and NOAEL for GA and that there was evidence (based on mean plasma-ChE values) of a dose-response relationship. Therefore, ORNL used that data to determine the LOAEL and NOAEL for ChE inhibition by GA. ORNL considered 56.25 µg/kg per day to be the LOAEL because of the significant reduction in plasma-ChE concentrations observed in male rats at this dose (relative to controls and baseline values). Because of the lack of consistent change in plasma- and RBC-AChE values (relative to controls and baseline values), ORNL considered the low dose of 28.13 µg/kg per day to be the NOAEL for the study. The subcommittee noted several weaknesses in using the Bucci et al.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents (1992) study to determine a NOAEL or a LOAEL for GA. The study involved the i.p. exposure route, which is not a relevant route of exposure for determining an RfD, 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. In addition, the methods used to measure ChE were not ideal (see Appendix G). The subcommittee considered other possible critical studies for the derivation of the RfD for GA. In a study by Dulaney et al. (1985), GA at 100 µg/kg was injected subcutaneously into rats daily for 85 days. Reduced growth rates were observed until day 38 of dosing, when rates returned to control levels. In addition, acetylcholinesterase (AChE) activity in the striatum and the remainder of the brain was 13% and 22%, respectively, of control values when measured 24 h after the last injection. The investigators also conducted a cumulative mortality study, in which rats were subcutaneously injected with GA at a dose of 70 or 100 µg/kg per day for 25 days. One animal from the low-dose group and two from the high-dose group died by day 20. The study was continued with the remaining rats for an additional 60 days, but no additional deaths occurred. The subcommittee found the Dulaney et al. (1985) studies to be even weaker than the Bucci et al. (1992) study for deriving the RfD for GA. Only one dose was used in the 85-day study and the only toxicity end points evaluated were growth rate and AChE activity in the brain. Similarly, even though the 25-day study included two doses, the only effect considered was mortality, an inappropriate end point for deriving RfDs. The subcommittee found no oral studies that involved repeated exposure to GA and no other suitable toxicity studies for deriving the RfD for GA. Thus, the subcommittee agrees with ORNL that the study by Bucci et al. (1992) is the most appropriate of the available studies for derivation of the RfD for GA. APPROPRIATENESS OF CRITICAL END POINT The NOAELadj (115 µg/kg per day) used by ORNL for derivation of the RfD for GA was based on the dose that did not cause a significant depression in plasma-ChE activity in rats (Bucci et al. 1992). The subcommittee notes that ChE inhibition is typically considered a biomarker of expo-

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents sure to organophosphate agents rather than an adverse effect. However, it is generally agreed that inhibition of ChE contributes 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). Although the subcommittee agrees with ORNL that ChE inhibition is a valid end point on which to base the RfD for GA, the subcommittee's confidence in the data is undermined by the increased baseline RBC-AChE concentrations, which were attributed to laboratory errors, in the critical study. Furthermore, confidence in the calculation of an equivalent oral NOAEL from an i.p. NOAEL is diminished because data from a secondary reference (i.e., RTECS 1995) were used to determine the ratio of the oral LD50 to the i.p. LD50. The subcommittee suggests that the data be verified from the primary source and cited appropriately. The subcommittee considered other possible toxicity end points, notably neurotoxicity, associated with GA exposure. Organophosphate compounds like GA 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. Emerging research in this area might indicate alternative toxicity end points to RBC-ChE inhibition that could be used to derive RfDs for nerve agents in the future. The subcommittee also notes that additional human data available on anti-ChE agents 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 directly applicable to deriving RfDs, they add to the completeness of the data base on GA. Provided that appropriate assays were used, the subcommittee finds no

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 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 GA. APPROPRIATENESS OF UNCERTAINTY FACTORS For GA, ORNL assigned values greater than 1 to four out of five uncertainty factors and 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) because no evidence suggests that humans are less susceptible than rats to GA. ORNL cited evidence that rodents have much lower RBC-AChE activity than humans (Ellin 1981), suggesting that rats might be more susceptible than humans to anti-ChE compounds, but also noted that the lower RBC-AChE activity might be offset by aliesterases (e.g., carbonyl esterase) present in the blood of rats. These enzymes, which are not found in humans (Cohen et al. 1971), are known to bind to and, therefore, reduce the toxicity of nerve agents (Fonnum and Sterri 1981). The subcommittee notes that rats have true ChE (AChE) in their plasma (Traina and Serpietri 1984), possibly reducing the toxicity of GA in rats. Furthermore, studies (Grob and Harvey 1958; Bucci and Parker 1992) with a similar nerve agent (GB) suggest that depression of RBC or plasma ChE with repeated oral administrations of nerve agents is much more difficult to induce in rats than in humans. The available data on GA are insufficient to evaluate species differences fully with regard to ChE activity in humans and rats. Few human acute toxicity data can be compared with the available data on the rat. However, ORNL noted that acute toxicity data are available for comparisons with monkeys (see Appendix A, Table 2). Although the data suggest that monkeys are more susceptible than rats to GA, such an evaluation is weakened by the fact that it is based on data from a secondary reference (i.e., RTECS 1995). The subcommittee suggests that the

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents original data cited in the secondary reference be verified and the primary reference cited appropriately. Nevertheless, the subcommittee notes that limitations exist in drawing any conclusions from this type of comparison because the data from monkeys are not necessarily directly applicable to humans and because the studies did not involve the oral route of administration and involved only single exposures. However, given the enzyme differences between humans and rats described above and the available data on GB (see Chapter 4), a similar nerve agent, the subcommittee agrees with ORNL that a factor of 10 is appropriate for interspecies extrapolation. 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 (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 that a factor of 10 is appropriate for protecting this susceptible subpopulation. EXTRAPOLATION FROM LOAEL TO NOAEL The subcommittee agrees with the identification of the NOAEL by ORNL and concurs that a factor of 1 should be assigned to the uncertainty factor for the extrapolation from a LOAEL to a NOAEL (UFL) because a NOAEL was used to calculate the RfD. EXTRAPOLATION FROM SUBCHRONIC TO CHRONIC EXPOSURES ORNL noted that in the derivation of RfDs for other organophosphate compounds, EPA (1989, 1992) used NOAELs for ChE inhibition that

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents were 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 GA, 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 data base on GA lacks a multigeneration reproductive toxicity study, a standard toxicity study in a second species, and toxicity studies by the oral exposure route. In addition, the subcommittee notes that some evidence indicates that GA might be weakly genotoxic, but no chronic exposure studies are available to evaluate the carcinogenic potential of GA. Because of those deficiencies, a factor of 10 arguably could be assigned for the uncertainty factor for data-base adequacy (UFD). Studies on other nerve agents, however, including a multigeneration study on VX (Goldman et al. 1988), two developmental toxicity studies on GB (Denk 1975; La Borde and Bates 1986), and a chronic inhalation study on GB (Weimer et al. 1979) indicate that reproductive, developmental, and carcinogenic effects are unlikely. Therefore, the subcommittee agrees with ORNL that a factor of 3 is adequate for UFD to account for the incomplete data base. MODIFYING FACTOR FOR ADDITIONAL UNCERTAINTY ORNL used a modifying factor (MF) of 3 to compensate for the uncertainty associated with the extrapolation of data from the i.p. to the oral route. The subcommittee also believes that an MF is necessary. In the subcommittee's judgment, the uncertainty associated with the route-to-route extrapolation was not great enough to warrant the use of a factor of 10 and, therefore, agrees with ORNL that a factor of 3 (the approximate logarithmic mean of 1 and 10) is appropriate.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents SUMMARY Table 3-1 presents the values assigned to the uncertainty factors and the modifying factor by ORNL and those recommended by the subcommittee. The subcommittee's recommendations are the same as those of ORNL. WEIGHT AND STRENGTH OF EVIDENCE The subcommittee believes that the strength of evidence for the Army's interim RfD of 4 × 10-5 mg/kg per day is weak, because the critical study (Bucci et al. 1992) used to calculate the RfD involved a nonoral route of exposure. CONCLUSIONS The approach used by ORNL to calculate the RfD for GA is consistent with the guidelines of the EPA. On the basis of available toxicity and related data on GA, the subcommittee concludes that the Army's interim RfD for GA of 4 × 10-5 mg/kg per day is scientifically valid. TABLE 3-1 Uncertainty Factors Used by ORNL and the NRC to Calculate the RfD for GA 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 1 1 UFS For subchronic-to-chronic extrapolation 3 3 UFD For data-base adequacy 3 3 MF Modifying factor for additional uncertainty 3 3 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; and UF, uncertainty factor.

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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 GA is the lack of subchronic or chronic oral toxicity studies from which to directly derive the RfD. The absence of oral data could be addressed by conducting a subchronic oral toxicity study that assesses anti-ChE activity in RBCs and plasma. Study of two species would be preferable. 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 to reassess the safety of the recommended RfD for GA. 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 National 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, J.A. Crowell, J.D. Thurman, and P.A. Gosnell. 1992. Toxicity Studies on Agent GA (Phase II): 90 Day Subchronic Study of GA (Tabun) in CD Rats. Final Report. DTIC AD-A258042. Prepared by Pathology Associates, Inc., National Center for Toxicological Research, Jefferson, Ark., for the 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. 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. Dulaney, M.D., Jr., B. Hoskins, and I.K. Ho. 1985. Studies on low dose subacute administration of soman, sarin and tabun in the rat. Acta Pharmacol. Toxicol. (Copenhagen) 57(4):234–241. EPA (U.S. Environmental Protection Agency). 1989. Ethion Reference Dose for

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 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). Ellin, R.I. 1981. Anomalies in Theories and Therapy of Intoxication by Potent Organophosphorus Anticholinesterase Compounds. Special Publication USA-BML-SP-81-003. DTIC AD-A101364. U.S. Army Medical Research and Development Command, Biomedical Laboratory, Aberdeen Proving Ground, Edgewood, Md. 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. 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. 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, Ark., 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 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

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Ed. EPA-540/9-88-001. Health Effects Division, Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington, D.C. 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 GA. 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. 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. U.S. Department of the Army. 1974. Chemical Agent Data Sheets, Vol.1. Edgewood Arsenal Special Report EO-SR 74001. Defense Technical Information Center, Alexandria, Va. Weimer, J.T., B.P. McNamara, E.J. Owens, J.G. Cooper, and A. Van de Wal. 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, Edgewood, Md.