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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A: Health Risk Assessment for the Nerve Agent GA
A: Health Risk Assessment for the Nerve Agent GA
Pages 97-130
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From page 97... ...
Appendix A Health Risk Assessment for The Nerve Agent GA
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From page 98... ...
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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Oak Ridge, Tennessee 37831 Submitted to Material/Chemical Risk Assessment Working Group Advisory and Coordinating Committee Environmental Risk Assessment Progra * Managed by Lockheed Martin Energy Research Corp.
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100 DRAFT A~MY~/SWASSESSMEW~SFO~ CHEM/CAI _~VA~FA~EAGEW~S AGENT GA DISCLAIMER This document is an internal review draft for review purposes only and does not constitute U.S. Government 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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11 4. ORAL REFERENCE DOSE FOR GA 13 4.1 Cholinesterase Inhibition as an RfD Endpoint 13 4.2 Derivation of the Oral RID 14 4.3 Overall Confidence in the Oral RfD 17 4.4 Comparison of the RfD with Human Toxicity Data 17 5.
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LD50 values for agent GA Table 3. RBC-AChE levels in 90-day subchronic rat study using agent GA Table 4.
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77-81-6; Edgewood Arsenal No.
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, 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.
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From page 106... ...
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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From page 107... ...
. 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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. These differences in RBC-AChE activity may affect a species' sensitivity to a particular organophosphate compound.
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. In addition to the immediate toxicity of the nerve agents, there is concern that acute exposures may lead to chronic neurological effects similar to those reported for some related organophosphate insecticides.
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. However, the available data on the organophosphate insecticides suggest that long-term toxicological effects do not occur in the absence of significant changes in blood cholinesterase activities, and a similar conclusion is likely to apply to the nerve agents.
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Mean baseline values for both male and female rats were elevated substantially (5029 versus 1848 IU1L in females and 4045 versus 1552 IU/L in males) when compared to control levels recorded in previous nerve agent studies conducted at the same laboratory.
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RBC-AChE levels in 90 day subchronic rat study using agent GAa Dose _ (pg/kg/d) Sex _ _ O F 1 28.13 F | 56.25 F 112.50 F O M 28.13 M 56.25 ~M 112.50 M Week of treatment 1 | l | %b | 3 | %b | 7 | sob | 13 | %b ~ _ ~ _ _ 3181(331)
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_ _ . Table 4 Plasma-ChE levels in 90 day subchronic rat study using agent GAa , Dose Wkg/d)
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Limited animal data indicate that such effects are unlikely. In studies in which CD rats were injected intraperitoneally with 0, 75, 150, or 300 lug GAILg/day on gestation days 6-1S, no fetal malformations or developmental effects (with the exception of increased pre-implantation losses relative to controls)
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4. ORAL REFERENCE DOSE FOR GA 4.1 Cholinesterase Inhibition as an RO Endpoint The endpoint for defining a maximum acceptable exposure level for nerve agents such as GA is considered to be the level at which no significant depression in blood cholinesterase activity occurs.
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From page 116... ...
4.2 Derivation of the Oral Rim for GA For the derivation of a chronic oral RfD, chronic or subchronic human oral exposure data are preferred; however, the only available human data for GA pertain to acute exposures. Although such data can be used to establish short-tenn exposure limits, acute toxicity endpoints are generally not used for developing subchronic or chronic reference values since they do not provide information on the possibility of cumulative effects following prolonged exposures.
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The only significant changes observed in the dosed animals were decreases in blood ChE activity levels. In the case of RBCAChE levels, considerable fluctuations occurred between and within test and control groups (0 ~glkg/day)
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An uncertainty factor of 3 is used to extrapolate from a subchronic to chronic exposure. 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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From page 119... ...
These studies generally support the use of cholinesterase inhibition as the critical endpoint for deriving an oral RfD. Deficiencies in the data base include the lack of a multi-generation reproductive toxicity study, a standard toxicity study in a second species, and toxicity studies by the oral exposure route.
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20 Day _ -_ ad a concen~ion of 50 mg-mi^3 (Reused unpublished d-.
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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 neIve agent exposure.
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U.S. Army, Medical Research Laboratory, Edgewood Arsenal, Aberdeen Proving Ground, MD.
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1962. Plasma and red blood cell cholinesterase activity as indications of the threshold of incipient toxicity of ethyl-p-nitrophenyl thiobenzenephosphorate (EPN)
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1995b. Oral RfD Assessment for Ethion.
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1984. Delayed neuropathy by the organophosphorus nerve agents soman and tabun.
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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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GA - RE) C-AChE Inhibition in Female Rats (ANOVA and Dunnett's)
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GA - Plasma-ChE Inhibition in Male Rats (ANOVA and Dunnett's)
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From page 130... ...
. Prepublication Copy 130 Oral Reference Doses
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