Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces (1996) / Chapter Skim
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5: THE STUDY AND MANAGEMENT OF INTERACTIONS
5: THE STUDY AND MANAGEMENT OF INTERACTIONS
Pages 52-68
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From page 52... ...
The suggested procedures and research strategies involve the use of civilian systems that are already in place, the increased computerization of military and VA records to monitor both exposures and outcomes, increased linkages between databases, and careful design and conduct of experimental and epidemiologic studies. KNOWN INTERACTIONS The completed matrices, described in Chapter 4, will display known interactions.
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From page 53... ...
Studies can then be extended to in vivo animal models with appropriate species and experimental designs.
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From page 54... ...
According to a recent National Research Council report (1994a) entitled Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms, the estimated exposure dose to a soldier in the Persian Gulf War was 6.8 x 10 mg/kg/day.
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From page 55... ...
The research elements needed to identify unanticipated adverse effects include an enhanced emphasis on toxicological screening studies focused on interactions and an increased surveillance in epidemiologic settings. With regard to surveillance, the identification of sentinel cases may indicate rare reactions to single agents as well as unpredictable or unusual interactions among multiple compounds.
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From page 56... ...
Ideally, for the most complete assessment of the potential interactions of drugs, biologics, and chemicals in U.S. military forces, a process such as the following should be adopted.
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From page 57... ...
other mathematical and statistical modeling tools. An advance in the pharmacokinetic and pharmacodynamic modeling of chemical carcinogenesis is the expression, in terms of fundamental cell cycle kinetics and within the framework of a linear multistage model for cancer of events, of the character of the biological processes governing cell replication and cancer (El-Masri et al., 1996; Thomas et al., 1996~.
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From page 58... ...
Data Analytic Approach In addition to animal toxicity studies, careful data analysis is also needed. Recent advances in statistical methodology, discussed below, allow for the eff~cient detection of interactions by malting use of data from studies with single agents.
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From page 59... ...
The real strength of this approach is that relatively few data are required to implement it. Under the assumption of additivity, in particular, the estimated dose-response surface can be calculated from the dose-response curves for the single agents; such data are likely to be available as a result of earlier product development research.
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From page 60... ...
With suitable preclinical models, the methods described above can be extended from animal toxicology studies to human studies, permitting the design and analysis of prospective studies that can test directly the existence of interaction effects when evaluating the potential health consequences of exposure to combinations of drugs, vaccines, and chemicals. Again, it is possible that many of the single-agent data are already available as a result of the research done in evaluating the individual agents.
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From page 61... ...
Therefore, it is necessary to use surveillance systems to supplement the information gathered by the above strategy. Surveillance This section describes approaches to monitoring exposures, identifying adverse health events, and investigating disease-exposure relationships in military personnel.
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From page 62... ...
Currently, the military is assembling data from the Persian Gulf War for a database to be linked with the personnel location database. This database includes environmental and meteorological data (e.g., air quality data in the area of the oil fires)
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From page 63... ...
The additional conditions should cover the categories of expected toxicities identified in the matrix analyses described in Chapter 3. For example, the category necrologic toxicity might include necrologic diseases like multiple sclerosis; the category immunological toxicity might include immune-suppression-related diseases like herpes poster, autoimmune-related diseases like systemic lupus and thyroid disease, and hypersensitivity-related diseases; the category liver toxicity might include acute liver injury; the category nephrotoxicity might include acute renal failure, and so on.
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From page 64... ...
3. Use the available reporting systems in the civilian sector, VAERS and MEDWatch, as alerting mechanisms to identify potential interactions that should be studied.
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From page 65... ...
, looking for differences in the exposures of the two groups. They can be done relatively inexpensively to investigate any marked increase in a sentinel event identified through the reportable diseases program.
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From page 66... ...
Selected birth defects that are rarely fatal yet are distinct enough to be identified at birth are less problematic for study than all birth defects. Adverse reproductive outcomes are not uncommon in pregnancy and usually carry no unique characteristics that would link them to the exposures, with the possible exception of unusual congenital malformation syndromes.
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From page 67... ...
This type of study can be used to assess the effects of agents that are known to interact but whose use cannot be avoided in field operations, those that have potential interactions, and those whose potential for interaction is as yet unknown. For example, this is one of the strategies being used to evaluate the health effects of the Persian Gulf War; hospitalization data have been compared for deployed and nondeployed personnel.
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From page 68... ...
The advice of experts in the fields of toxicology, epidemiology, and pharmacology will be needed on a continuing basis to assist military scientists and program managers in developing experimental approaches, selecting model systems, designing epidemiologic studies and surveillance programs, and providing information during policy discussions concerning the costs and benefits of potential decisions. An expert advisory panel established under a chartered advisory structure, such as the Armed Forces Epidemiology Board, and comprising experts in the several needed disciplines could provide the appropriate advice and guidance to the military research community, those who perform preventive medicine activities, and health care providers.
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