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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D: Health Risk Assessment for the Nerve Agent VX
D: Health Risk Assessment for the Nerve Agent VX
Pages 197-234
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From page 197... ...
Appendix D Health Risk Assessment for The Nerve Agent VX
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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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External review of the toxicity data was provided by Dr. Thomas J
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B-1 RBC-AChE Inhibition in Rats Dosed with VX C-1 APPENDIX D Oral RfD Estimated Mom Human Data D-1 .
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RBC-ChE activity in rats injected subcutaneously with VX Table 4. Regression analysis of Rice et al.
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, 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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The degradation product, methyl phosphoric acid, was detected at concentrations ranging from 14.9 to 23 ,ug/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 ~g VX per 900 gm of solid material [estimates based on an assumed 100% extraction efficiency (Sass et al., 1970)
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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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. 2.2.1 Intra- and Interspecies Vanation 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.
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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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. 2.2.2 Potency of Nerve Agents as Cholinesterase Inhibitors The potency of the anticholinesterase activity of nerve agents and other organophosphates is measured by either the bimolecular rate constant (ki)
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do not occur in the absence of significant changes in blood cholinesterase. The same conclusion may apply to the organophosphate nerve agents.
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injection of 0.04 ~g/kg in one adult test subject caused headaches, tiredness and irritability, but no change in RBC or whole blood cholinesterase activity. A subsequent 30-see i.v.
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, hematology, body and organ weights, or gross or microscopic pathology. Whole blood ChE activity levels were monitored prior to the first exposure (one determination per animal)
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, and 10 animals of each sex were sacrificed at 90 days. RBC-AChE activity levels were monitored in 2 of 5 or in 3 of 10 animals per sex at each of the sacrifice times; blood chemistry was evaluated in the remaining animals.
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. Chickens injected subcutaneously with supralethal doses of VX (10, 100, or 150 ~g/kg, following treatment with antidotes to protect against acute toxicity)
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None of the lambs displayed neurotoxic signs or symptoms, and their whole blood cholinesterase activity was not reduced even when suckling from exposed and affected ewes. Five months after exposure, the ewes exposed in the field as well as ewes dosed with an undisclosed amount of VX four months previously, were mated to unexposed males.
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Blood cholinesterase activity levels were not monitored during the study. VX exposure had no adverse effect on the number of pups born in the F1 or F2 generation.
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. In addition, 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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Whole blood ChE was significantly depressed at all dose levels (levels of significance not reported) without any physical signs of clinical toxicity in any dose group.
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. [Note: in sheep, about 90% of the blood ChE activity is in the RBC fraction (Osweiler et al., 1985)
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In the derivation of oral RfDs for other organophosphate compounds, EPA has used NOAELs for cholinesterase inhibition following short-term exposures without adjustment for a more prolonged exposure period because of the unlikelihood that the endpoint would change over time (i.e., a subchronic-to-chronic UP of 1 was used)
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0.961742 0.836172 0.930412 0.90184 0.46 0.76 1.90 1.94 2.26 1.97 0.993047 0.940522 0.980956 2.08 0.969214 1.86 2.45 a Data analysis based on four time points at which ChE inhibition stabilized b Based on %ChE inhibition at 3, 9 and 15 ~g/kg/day (see Appendix B) c Denved from means for 744, 912, 1176, and 1320 hr 4.3 Overall Confidence in the RfD Study: Medium Data Base: High RfD: High The data base for VX consists of subchronic studies in sheep and rats, teratology studies in rats and rabbits, a modified dominant lethal study in rats, a delayed neuropathy study in chickens, and a multigeneration study in rats.
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One study in humans indicated that an oral dose of 1.43 ~g/kg/day for 7 days resulted in a 60% RBC-AChE inhibition but no toxic effects (Sim et al., 1964)
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1951. Blood cholinesterase levels and range of personal variation in a healthy adult population.
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1992. Characterizing biological variability in livestock blood cholinesterase activity for biomonitoring organophosphate nerve agent exposure.
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U.S. Army, Chemical Corps Research and Development Command, Chemical Research and Development Laboratories, Army Chemical Center, MD.
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Technical Report DTC 71-512, Deseret Test Center, Dugway Proving Ground, Dugway, UT. Rickett,D.J.,J.F.Glenn,W.E.Houston.
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U.S. Arrny Chemieal Corps Research and Development Command, Chemieal Researeh and Development Laboratories, Army Medical Center, MD.
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1976. Components of variability in blood cholinesterase assay results.
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(c) in vitro Acute toxic effects in 20-30 2-4.5 humans/oral dose human oral LD50 25 50b 5 20b 5-20 3-1Ob (estimated)
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(1971) Data for Sheep Dosed with VX `F E · E O E 1 .
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APPENDIX D: HEALTH RISK ASSESSMENT FOR VX DRAFT 231 AGENT VX APPENDIX C STATISTICAL ANALYSIS OF RBC-AChE INHIBITION IN MALE RATS DOSED WITH VX Study: Goldman et al., 1988 Species Sprague-Dawley rationales Eadpou~t: RBC |
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232 DRAFT A~MYR/SWASSESSME7V~SFOW C~EM/CAI _/~A~FA~EAG~WTS AGEN r vx _ APPENDLY C STATISTICAL ANALYSIS OF RBC-AChE INHIBITION IN FEMALE RATS DOSED WITH VX Stud~r: Goldman et aL, 1988 Species~ Sprague-Dawley rats/females Endpoint: RBC |
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UF4 = 10 (LOAEL to a NOAEL extrapolation) ; 60% inhibition is near a level where physical signs of clinical toxicity may occur.
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Prepublication Copy 234 Oral Reference Doses
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