Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents (2005) / Chapter Skim
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3 Review of the Department of Defense Master Research Plan on Low-Level Exposure to Chemical Warfare Agents
3 Review of the Department of Defense Master Research Plan on Low-Level Exposure to Chemical Warfare Agents
Pages 30-64
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From page 30... ...
applicable to humans that are indicative of early effects on operationally relevant performance decrements or potential delayed adverse health effects after low-level exposure to anticholinesterase nerve agents and other CWAs, especially during military operations, and (2) to identify strategies for use of the research data for human health risk assessment.
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OVERVIEW OF THE DOD'S CURRENT RESEARCH PLAN The DOD Research Plan states that the nerve agents (G-series agents tabun [GA] , sarin [GB]
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The primary question addressed by the committee was, "Do the studies that DOD proposed in its Research Plan match the objectives stated above? " DOD is particularly interested in generating research data that can be used for human health risk assessment and risk management.
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The goal of this research task for agent GB is to demonstrate a dose-response relationship for unequivocal end points of operational significance and to validate or refute the historical database for short-duration exposures. An extension of this goal is to provide new
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exposure by conducting experiments with and without eye protection. Also, during experiments examining effects of nerve agents on the eye, it should be possible to examine selected behavioral end points under various ambient light conditions as well.
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From page 35... ...
Experimental studies in which CWAs are instilled in the eyes, with appropriate dose ranges for correlation with cholinesterase inhibition in the eye, may be informative. While blood cholinesterase inhibition may not always correlate with functional changes after CWA exposure, it is a reasonable expectation that miosis and cholinesterase inhibition in the sphincter muscle controlling pupillary constriction will correlate.
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From page 36... ...
Information on interspecies relevance of this end point was not provided in the DOD plan or in DOD presentations to the committee, although it was suggested that the EC50 for miosis in humans exposed to nerve agents is approximately equivalent to that in minipigs. This is supported by information in the 2003 NRC report.
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From page 37... ...
Acute exposure guideline levels (AEGLs) for exposures from 10 minutes to 8 hours are available for the nerve agents GA, GB, GD, GF, and VX (NRC 2003)
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These tasks are discussed below. Task IB1: GB Vapor Generation and Chamber Systems The goal of this research task is to overcome technical challenges to generate consistent vapor atmospheres for GB and relate fairly robust historical generation data to modern, validated chamber-exposure methodology.
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to develop 24-hour military exposure guidelines (MEGs) for nerve agent and HD from the 8-hour AEGLs (i.e., assuming Haber's law that Ct = k for expo
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Subthrust IIA: Identify Acute Pathological Health Effects Resulting from Low-Level CWA Exposures This subthrust is subdivided into the following five tasks:
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The MTD for the nerve agents of interest and the application of these data to follow-up neurobehavioral, pathophysiologic, and toxicogenomic studies is detailed in the Research Plan (pp.
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DOD believes data from these studies will identify more subtle alterations in central and peripheral nervous system function due to CWA exposure. Committee's Evaluation, Conclusions, or Recommendations for Task IIA2 The committee concludes that animal studies focusing on alterations in behaviors are difficult to use when extrapolations must be made across species and to humans.
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This institute has studied EEG, visual evoked responses, and miosis in guinea pigs and marmosets and has considerable experience in inhalation exposures for nerve agent exposure as well as analytical capabilities. Regardless of the behavioral tests to be used, the committee recommends that consideration be given to evaluating possible adaptive changes in behavior after repeated low-level exposures to CWAs and that the connection between measured changes and overt clinical and behavioral effects be evaluated.
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From page 44... ...
Task IIA3: Neurochemical and Immunohistochemical Changes in Rodents For this DOD research task, modern techniques will be used to identify changes in brain neurochemistry and cellular-level alterations in metabolism in rodents exposed to low-level chemical warfare nerve agents. According to DOD, data compiled from these studies will provide quantitative estimates of changes in brain chemistry and/or microscopic anatomy in response to chemical warfare nerve agents and will identify doses and durations of exposure required to induce the changes.
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From page 45... ...
For this research effort, DOD plans to study the origin of cardiac anomalies seen with chemical warfare nerve agents at low levels of exposures. According to DOD, cardiac failure appears to be a major contributor to nonpulmonary toxicity of these agents in susceptible individuals at low doses.
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The goal of this DOD research task is to conduct cognitive testing that will be performed in nonhuman primates with established low-level CWA exposures that show effects in rodents. According to DOD, the use of nonhuman primates will permit more sophisticated, computerized testing and will ensure that any observed effects can be extrapolated to human populations.
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According to DOD, the analysis of toxicogenomic data sets will identify doses of CWAs that induce alterations in metabolic homeostasis; it also will establish threshold exposures that have minimal or no effect and will indicate biochemical pathways affected by CWA exposures. For this research task, tissues from animals exposed via inhalation to CWAs are being evaluated to determine whether this end point will correlate with the Ct profile.
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From page 48... ...
DOD has included in its Research Plan other experiments that would provide new data of academic interest, but the length of time required to obtain validated end points would make them difficult to adapt for field conditions, especially when acute exposure is of interest. These experiments include the research in toxicogenomics and the research on the binding and recovery of nerve agents from exposed tissues.
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From page 49... ...
With MTD defined by DOD as the upper limit of exposure without clinical signs, the nonlethal, repeated MTD of nerve agents is approximately 0.2-0.4 LD50 per day. Nonlethal effects from exposure to repeated dosages greater than or equal to MTD
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Results from animals exposed by inhalation or parenteral routes will be correlated with each CWA profile for the determination of operationally significant effects. According to DOD, findings from these studies will also indicate the potential risk due to low-dose CWA exposures of persistent or delayed-onset neuropathology that could produce long-term disabilities.
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The committee concludes that such research in laboratory animals by DOD might have limited relevance because, if there are performance decrements, they would be quite subtle and difficult to differentiate from control animals. Task IIC2: Synaptic Receptor Density up to One Year Postexposure For this DOD research plan, rodents previously exposed to CWA nerve agents for short-term exposures will be periodically examined after exposure, and brain levels of cholinesterase, muscarinic acetylcholine receptors, and other targeted proteins will be quantitatively determined.
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Task IIC3: Immunohistochemistry and Neuron Density up to One Year Postexposure For this DOD research task, the characteristics of brain neurons after exposure will be monitored during and after short-term exposure to chemical warfare nerve agents. Alterations in immunohistochemical staining in existing cells and overall cell number will be monitored after exposure to identify whether any cell populations are selectively affected by the CWA and whether these cells degenerate over time or recover function.
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Although some investigators consider gender differences in plasma cholinesterase activity to be confined to young persons (reviewed by NRC 2003) , data are available suggesting that adult females may be more susceptible than males to nerve agents.
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According to DOD, this research might be used to identify specific ionic channels/biochemical pathways that are highly susceptible targets for chemical warfare nerve agents at low levels, and
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In particular, the committee encourages research on "interactions of different CWA with cardiac muscarinic receptors and changes in cardiac function" and also possible low-dose effects on myocardial Na+/K+-ATPase. By contrast, Task IID2 calls for the use of computer models to identify "ionic mechanisms that undergo failure" due to CWA exposure in order to "identify specific ionic channels/biochemical pathways that are highly susceptible targets" for CWA.
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Task IIIA1: Cross-Species Dosage Comparison and Task IIIA2: Pharmacokinetic Model Development of Agent Distribution Fate The goal of DOD Task IIIA1 is to demonstrate chemical warfare nerve agent equivalents for two or more experimental animal model systems in predicting well-established end points (e.g., lethality) and compare routes and species dose-response relationships to reconcile historical data sets.
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PBPK models can help to address these uncertainties as well as help address differences in breathing rate between experimental and operational conditions; the development of criteria for evaluating PBPK models is important. One of the key aspects of such models would be to ensure that the model provides information on dose metrics relevant to the critical end points.
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From page 58... ...
The proposed biomarkers/dose metric to be studied includes alkyl phosphonates, regenerated nerve agent, AChE activity, and butyrylcholinesterase activity. Sites monitored would be relevant to the development of pharmacokinetic models that include blood, lungs, kidney, adipose tissue, brain, muscle, and liver.
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From page 59... ...
The committee recommends that future efforts on this task be focused on the regenerated nerve agent method for biomonitoring exposures. The committee supports the intent of research Task IIIB1, which calls for developing a "consistent marker in body tissues that is directly related to the absorbed dose." On the other hand, it is not clear that such a marker will necessarily correlate with all physiological effects of exposure or at all dose levels, as implied in the task description.
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Another method for detecting exposure to nerve agents involves electrospray tandem mass spectrometric analysis of phosphylated nonapeptides obtained after pepsin digestion of butyrycholinesterase from human serum samples (Fidder et al.
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However, because the major goal of DOD research is to determine exposure levels that could lead to operationally relevant performance decrements and delayed health effects and the exposures to be modeled are for low doses, which are likely to produce subtle changes at most, those methods might not provide information of highest priority for the objectives of this research program. The committee recommends that, with the limited resources and time available for completion of the proposed research, less emphasis be placed on continuing the research proposed in this task.
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The committee recognizes that a considerable amount of research has been done and much information is available on the acute (shortterm, high-level exposures) and subchronic toxicity of nerve agents and HD.
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To obtain the information most valuable in detecting and protecting military personnel from operationally significant decrements or potential delayed adverse health effects after short-term exposures to low levels of CWAs, DOD should ensure that the total database from previous human and animal studies has been fully examined to fill data gaps. These include specific studies done with human subjects (NRC 1982, 1985)
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From page 64... ...
The committee concludes that DOD's Master Research Plan on low-level exposures to CWAs, in general, is well planned and many of the proposed research tasks are likely to provide valuable information to DOD in protecting military personnel from low-level exposures to CWAs, in terms of avoiding performance decrements and delayed health effects. The Research Plan includes some studies that have some potential to identify delayed adverse health effects, but those studies should be assigned lower priority in the context of DOD's primary objectives.
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