Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents (2005) / Chapter Skim
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4 Research Issues Related to Risk Assessment of Low-Level Exposure to Chemical Warfare Agents
4 Research Issues Related to Risk Assessment of Low-Level Exposure to Chemical Warfare Agents
Pages 65-88
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4 Research Issues Related to Risk Assessment of Low-Level Exposure to Chemical Warfare Agents As noted earlier, one charge to the committee was to review and consider the U.S. Department of Defense's (DOD's)
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HOW MUCH OF A DECREMENT IN THE CRITICAL RESPONSE IS ADVERSE? In the military operational risk management (ORM)
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RESEARCH ISSUES RELATED TO RISK ASSESSMENT 67 individuals (people who have lost elasticity of the lens due to advancing age) under well-lit conditions, a finding attributed to the pinhole effect, but miosis would decrease visual acuity in dim light (Sidell 1977)
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Although the uses of biomarkers described in this report may have limited relevance to immediate ORM decisions, it is likely they might be useful for research on postexposure sequelae, for refining interspecies extrapolations, and for exposure reconstruction (the DOD Research Plan only mentions biomarkers briefly)
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RESEARCH ISSUES RELATED TO RISK ASSESSMENT 69 phisms for determining tissue dose (and therefore risk) depend on the degree to which enzyme activity limits metabolism (Gentry et al.
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Empirical curve-fitting methods can also be used if the data span the time period of interest. Physiologically based pharmacokinetic (PBPK)
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The National Research Council (NRC)
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72 REVIEW OF THE DOD RESEARCH PROGRAM ON CWAs For military operations, the U.S. Army Center for Health Promotion and Preventive Medicine (USACHPPM)
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Those commanders will only rarely find that traditional formats for presenting toxicologic data meet their needs. Accordingly, one of the challenges of the DOD research program will be to find ways to express or relate relevant data in adequate and useful ways that consider both the need to adequately protect forces from the harmful effects of low levels of CWAs and the offsetting costs of impairing the capacity of forces to accomplish their battle objectives consequent to the use of protective gear or MOPP.
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However, multiple CWAs might be simultaneously deployed. In the development of AEGLs for nerve agents, the National Research Council (NRC)
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RESEARCH ISSUES RELATED TO RISK ASSESSMENT 75 Existing and well-conducted experimental studies indicate that the toxicity of G-series nerve agents is additive. Relative-potency analyses documented in the NRC (2003)
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(1988) developed a physiologically based pharmacodynamic (PBPD)
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RESEARCH ISSUES RELATED TO RISK ASSESSMENT 77 when the dose of C(+/-)
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that would be needed in operational risk assessment. Experimental design consideration of adequate size for each exposure-response group would help minimize uncertainties in subsequent extrapolations.
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80 REVIEW OF THE DOD RESEARCH PROGRAM ON CWAs Variability in nerve agent kinetics is due to genetic factors, such as polymorphisms in the paraoxonase gene (PON1) , as well as variability in expression of the relevant enzymes (Furlong et al.
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RESEARCH ISSUES RELATED TO RISK ASSESSMENT 81 rial experimental design where combinations of concentrations and durations are tested. Table 4-2 provides an example of a better experimental design that more specifically targets the experimental data points to provide the most information on the dose-response.
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82 REVIEW OF THE DOD RESEARCH PROGRAM ON CWAs 1 8.0 ytilibaborP 6.0 4.0 2.0 0 20 15 60 50 Duration 10 40 Concentration 30 5 20 10 0 0 FIGURE 4-2 Perspective plot of hypothetical data assuming Haber's law applies (using parameter values = -2.944439, ß = 0.009036316 in equation 1)
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RESEARCH ISSUES RELATED TO RISK ASSESSMENT 83 logit[ (C, t)
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84 REVIEW OF THE DOD RESEARCH PROGRAM ON CWAs 1 8.0 ytilibaborP 6.0 4.0 2.0 0 20 15 60 50 Duration 10 40 Concentration 30 5 20 10 0 0 FIGURE 4-4 Perspective plot of hypothetical data assuming Haber's law does not apply (using parameter values = -2.944439, ß = 0.009036316, = 0.3 in equation 2)
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RESEARCH ISSUES RELATED TO RISK ASSESSMENT 85 when Haber's law does not apply. For example, a concentration = 20 × duration = 10 (units arbitrary)
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86 REVIEW OF THE DOD RESEARCH PROGRAM ON CWAs Y = + ß (Cn × t) + error.
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Field commanders ultimately must be able to use the information generated by this research program to make decisions. The DOD toxicology establishment should confer with operations personnel to determine the nature and form of information that would be most useful.
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For CWAs, for each critical response (e.g., miosis) , access to recently generated experimental data sets and contact with investigators should be pursued to develop other response probabilities that would be needed in operational risk assessment beyond single values, such as ECt50 or EC01 (e.g., 15%, 30%, 40%)
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