Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents (1999) / Chapter Skim
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B: Health Risk Assessment for the Nerve Agent GB
B: Health Risk Assessment for the Nerve Agent GB
Pages 131-166
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Appendix B Health Risk Assessment for The Nerve Agent GO
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. Exposure to some organophosphate cholinesterase inhibitors results in a delayed neuropathy characterized by degeneration of axons and myelin.
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I ASK ASSESS POR =~ AGES GB DINT _0= Set 1996 (edl~Hal cowhides made ^phl 1997)
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134 Dig _ ~-~ ^G~ GB DISCLA=ER b document h ~ intem~ review dam far review purposes only Ad does not cony U.S. Govemmen1 policy.
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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)
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....................... 2 2.2.1 Intra- and Interspecies Variation in Blood Cholinesterase Activity 5 2.2.2 Potency of Nerve Agents as Cholinesterase Inhibitors 6 ........................................
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RBC-ChE levels in 90-day subchronic study of GB type II in CD rats Table 5. Plasma-ChE levels in 90-day subchronic study of GB type II in CD rats Table 6.
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107-44-8; Edgewood Arsenal No.
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. Studies conducted with soil samples from Dugway Proving Ground and Edgewood Arsenal showed that 90% of GB added to soil and maintained in closed containers at room temperature (20-25°C)
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. Exposure to some organophosphate cholinesterase inhibitors results in a delayed neuropathy characterized by degeneration of axons and myelin.
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, and this is reflected in the fact that blood cholinesterase activity may not always be correlated with exposure or with signs and symptoms of toxicity. Acute exposures to high concentrations may cause immediate toxic effects before significant changes occur in blood ChE activity, and repeated exposures over a period of several days may result in a sudden appearance of signs and symptoms due to cumulative effects (Grob and Harvey, 1958)
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A small subpopulation of men and women have a genetic defect causing their blood cholinesterase activity to be abnormally low (Evans et al., 1952; Harris and Whittaker, 1962)
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. In addition to the immediate toxicity of the nerve agents, there is concern that exposures may lead to chronic neurological effects similar to those reported for some organophosphate insecticides.
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3.2 Acute Toxicity In tests on humans, Grob and Harvey (1958) found that a single oral dose of 0.022 mg GB/kg produced mild toxic effects including anorexia, nausea, heartbun~, tightness in the stomach and chest, increased fatigue, nervous tension, anxiety, and other CNS responses including insomnia and excessive dreaming.
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I 995 aValues for humans estimated from animal data bBased on 70 kg body weight CLethal level Grob and Harvey (1958) also administered to human volunteers multiple oral doses of GB over a period of 3 days (3-24 hr apart; average 7.5 fur)
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in female rats dosed with 0.3 mg/kg/day GB Type I The latter, however, did not exhibit any histological signs of delayed neuropathy.
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Male rats exposed to the lowest dose of GB Type II exhibited a 38% decrease in RBC-ChE activity in week 1; females exhibited a 12% decrease. By week 13, RBC-ChE activity levels 10
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Plasma ChE levels in Heyday subchronic study of GB Type II in CD ratsa Dose I Sex 1 .
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There are no animal studies involving chronic oral exposures to GB. In chronic inhalation studies conducted by Weimer et al.
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Control 0/10 4/10 Dose group . I 0.0001 mg/m3 1 0.001 mg/m3 5/10 0/10 0/10 9/10 0/10 5/8 o/g 0/10 1/10 0/10 0/5 2/6 24 10 1/5 1/10 36 ot9 2/5 2/7 52 2no Ino 6no 11 1 0/20 6-month post~exposurc 7/19 ens Totals 3/108 25/98 34/108 Source: Weimer et al., 1979 3.5 Nervous System Toxicity A~MYR/S~ASS~SSMEA/~SFOW C~M/CAI _//VA~FA~EAGEW~S AGENT GB As noted in Section 3.1, the neurotoxic effects following acute exposures to nerve agent such as GB can range from minor symptoms such as fatigue, headache, mild vertigo, weakness, and loss of concentration to convulsions, respiratory arrest, and death.
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Skeletal and cartilage variants occurred between dose group but these were not statistically significant. In similar studies conducted on New Zealand rabbits using the same experimental protocol, oral doses of 0, 5, 10, or 15 ~glkg/day on gestational days 6-19, resulted in no fetal toxicity or teratogenicity (Laborde and Bates, 1986)
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3.7 Carcinogenicity There are no human data to suggest that GB is carcinogenic. As part of chronic inhalation studies conducted by Weimer et al.
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. Animal data have shown that exposure to low doses of nerve agents for extended periods of time can result in low blood ChE activity levels without signs of toxicity.
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. Although no other toxic effects were observed in the rats dosed with GB Type II, brain lesions (hippocampal necrosis)
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In the Bucci and Parker study plasma and RBC-ChE activity levels at week 13 were no longer significantly different from both baseline and control values, particularly for the lowest dose level (see Appendix B) ; therefore, increased ChE inhibition is not expected to occur at longer exposure periods.
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The data base for GB also contains a second oral subchronic study in rats, chronic inhalation studies in rats, mice and dogs, teratology studies in rats and rabbits, and delayed neuropathy studies in mice and chickens. Deficiencies in the data base consist primarily of a lack of a multi-generational reproductive toxicity study, and a standard toxicity sn~dv in a second species.
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Route EndpoiDt 0.02 oral RfD - no inhibition of RBC-AChE . 2 oral excessive dreaming 23 oral; average daily dose RBC-AChE reduced 27 and 33°/4 but no toxic effects for three days 10 oral 50°/O inhibition of AChE 20 oral insomnia, withdrawal, depression 22 oral mild toxic effects, anorexia, nausea, heartburn 29 oral; average daily dose mild toxic effects for three days 30 oral moderate toxic effects 34 oral; average daily dose moderate toxic effects; > 90% reduction in RBC for three days AChE activity 1 .
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1951. Blood cholinesterase levels and range of personal variation in a healthy adult population.
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U.S. Army Medical Research and Development Command, Biomedical Laboratory, Aberdeen Proving Ground, MD.
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1992. Characterizing biological variability in livestock blood cholinesterase activity for biomonitoring organophosphate nerve agent exposure.
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Technical Report DTC 71-512, Deseret Test Center, Dugway Proving Ground, Dugway UT. Rickett, D.J., J.F.
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Technical Report 8304, AD A149515, US Army Medical Bioengineering Research and Development Laboratory, Fort Detrick, Frederick, MD. Somani, S.M., R.P.
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APPENDS B: HEALTH RISK ASSESSMENT FOR GB Dot __ _ e ~ I 00 At GB Win~olz, ad.
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(c) in vitro Acute toxic effects in 20-30 hwnans/oral dose ~ human oral LD50 25 50b 5 20b 5-20 (estimated)
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GB Type II - Plasma Cholinesterase Inhibition in Male Ratsa (ANOVA and Dunnett's Comparison)
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... GB Type II - RBC Cholinesterase Inhibition in Female Ratsa (ANOVA and Dunnett's Comparison)
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