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Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations (2020)

Chapter: 5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans

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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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Suggested Citation:"5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans." National Research Council. 2020. Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations. Washington, DC: The National Academies Press. doi: 10.17226/25837.
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5 Challenges and Opportunities for Advancing the Understanding of Respiratory Health Issues in Southwest Asia Theater Veterans Previous chapters of the report identified putative airborne hazards present in the Southwest Asia Theater of Military Operations and Afghanistan,1 described the respiratory health outcomes that might be associated with exposure to those hazards, and presented an evaluation of the scientific and medical evidence regarding the out- comes in military personnel who served in the theater. This chapter builds on the results of those efforts to offer insights on outstanding exposure and health questions and how the Department of Veterans Affairs (VA) could help to address them. ISSUES IDENTIFIED FOR THE COMMITTEE’S ATTENTION The committee’s Statement of Task from VA directed it not only to evaluate the evidence regarding in-theater airborne exposures and adverse respiratory health effects but also to offer observations and recommendations on how VA might generate information that would help it to make better informed decisions in the future. Specifically, it requested that the committee “pay particular attention to hazards associated with burn pit exposures” and use the results of its comprehensive review to “identify knowledge gaps, research that could feasibly be conducted to inform the field and generate answers, newly emerging technologies that could aid in these efforts, and organiza- tions that VA might partner with to accomplish this work.” The committee combined several sources of information to accomplish this task. These included its review of the studies of health outcomes in theater veterans (presented in Chapter 4), input from several subject-matter experts presented at an October 2019 workshop (listed in Appendix A and summarized in Chapter 3; all presen- tations are also posted to the web2), and the information and recommendations developed by previous National Academies committees that examined similar issues. The following sections address the Statement of Task issues in the order in which they were posed. 1  Hereafterreferred to as the Southwest Asia theater or theater, in keeping with the other chapters of this report. 2 See http://nationalacademies.org/hmd/Activities/Veterans/RespiratoryHealthEffectsofAirborneHazardsExposures/2019-OCT-3.aspx (ac- cessed August 24, 2020). 193

194 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES HAZARDS ASSOCIATED WITH BURN PIT EXPOSURES Literature Regarding the Health Effects of Exposure to Burn Pit Emissions Concerns have long been raised over the hazards associated with exposure to emissions from the open burn pits used in theater for waste management. These exposures have been the primary topic of four earlier National Academies reports, which are first summarized followed by a discussion of findings from newer research that was summarized in earlier chapters. Previous National Academies Reports Addressing the Health Effects of Exposure to Burn Pit Emissions The third volume of the report series Gulf War and Health contained a comprehensive review of the litera- ture addressing the association between exposure to fuels, combustion products, and propellants present in the 1990–1991 Gulf War theater and health outcomes (IOM, 2005). Combustion products were defined as “smoke from fires, exhaust from burning fuels, and products of other combustion sources” (IOM, 2005, p. 39), and it was observed that these are also constituents of air pollution in general. As noted in Chapter 4, the committee respon- sible for that report concluded that there was sufficient evidence of an association between combustion products and lung cancer and limited or suggestive evidence of an association between combustion-product exposure and oral, nasal, and laryngeal cancers and incident asthma. (Volumes 4, 8, and 10 of the series [IOM, 2006, 2010; NASEM, 2016b] addressed burn pit exposures but only as part of a larger examination of the health effects of service during the Gulf War—they did not draw specific conclusions about the association between these exposures in theater and health outcomes.) Responding to a request from the U.S. Army, the National Academies formed an expert committee to review a report (Engelbrecht et al., 2008) that summarized the results of the Department of Defense’s (DoD’s) Enhanced Particulate Matter Surveillance Program (EPMSP) (NRC, 2010). EPMSP was an effort to characterize and quan- tify particulate matter (PM) in the ambient environment at 15 sites3 in the Persian Gulf Region over 12 months in 2006–2007. That committee was also asked, among other tasks, to consider whether and how such data and other information collected by the U.S. Army Center for Health Promotion and Preventive Medicine (CHPPM) might be put to use in assessing the health outcomes of deployed personnel. It commended the effort but found that the design and conduct of EPMSP limited its usefulness in health studies. The committee concluded that it was plausible that exposure to airborne PM—which it defined as including burn pit emissions but also such sources as windblown dust, dust storms, and diesel exhaust—was associated with adverse health outcomes but that the interpretation of the information collected in theater was encumbered by uncertainties regarding the actual exposures, the small number of study subjects, and the limited amount of exposure data. It recommended that “[a] more complete inventory of all major sources of ambient pollutants and potential emissions in the theater should be constructed before assessment of health effects to ensure that all relevant pollutants are monitored” (NRC, 2010, p. 9). Of particular relevance to this report, the 2011 report Long-Term Health Consequences of Exposure to Burn Pits in Iraq and Afghanistan summarized the results of studies of health effects associated with exposures to 51 pollutants that were detected in air samples taken at Joint Base Balad in Iraq4 in 2007 and 2009 (IOM, 2011). There were a number of potential sources of these pollutants, and the committee that produced the 2011 report concluded that burn pits were not a major source of many of them. Because there were few studies on exposures of military populations to burn pits available at the time, that committee expanded its literature review to include examinations of surrogate populations whose members had occupational or residential exposures to combustion products, such as firefighters, incinerator workers, and those living near an incinerator. The committee used a 3  The 15 sites were in the following countries: Djibouti (one), Afghanistan (two, in Bagram and Khowst), Qatar (one), United Arab Emirates (one), Iraq (six, in Balad, Baghdad, Tallil, Tikrit, Taji, and Al Asad), and Kuwait (four, in northern, central, coastal, and southern Kuwait). 4  Joint Base Balad was one of the largest military bases in Iraq and a central logistics hub for U.S. forces there. Because of its large popu- lation, the scale of the Balad burn pit was also large, with estimates of the amount of waste burned ranging from about 2 tons per day early in its operation in 2003 to 200 tons of waste being burned daily in 2007 (APHC, 2010; Taylor et al., 2008). The burn pit ceased operating in late 2009 (IOM, 2011).

ADVANCING THE UNDERSTANDING OF RESPIRATORY HEALTH ISSUES 195 weight-of-evidence approach to determine the strength of the association between exposure to combustion products and each health outcome. The 2011 report concluded that there was inadequate or insufficient evidence of an association between exposure to combustion products and respiratory disease or cancer in general. It did find limited or suggestive evidence of an association between exposure to combustion products and reduced pulmonary function in the study populations, but it was unable to determine whether the long-term health effects were likely to result from service members exposed to emissions from burn pits—specifically the one in operation at Joint Base Balad—because high ambient concentrations of PM from both natural and anthropogenic sources likely modified the effects, but could not be accounted for or adjusted in the analyses. Therefore, that committee concluded that the long-term health risk of airborne toxicants, burn pit, and other related exposures was not clearly defined. The report stated that none of the individual chemical constituents of the combustion products emitted from the burn pit appeared to have been present at concentrations high enough to be responsible for any of the adverse health outcomes. However, it was also noted that “the possibility of exposure to mixtures of those chemicals raises the potential for health outcomes associated with cumulative exposure to combinations of the constituents in burn pit emissions” (IOM, 2011, p. 8). Moreover, given the limitations of the literature, the information “might not provide a comprehensive picture of the risks posed to military personnel from burn pit emissions” (IOM, 2011, p. 103). More recently, the 2017 National Academies report Assessment of the Department of Veterans Affairs Airborne Hazards and Open Burn Pit Registry included an update (through early 2016) of the scientific literature regarding long-term health outcomes in service members and veterans who served in the Southwest Asia theater (NASEM, 2017). Only four of the papers it identified addressed respiratory outcomes in populations where exposure to burn pit emissions was explicitly factored: Abraham et al. (2014), Liu et al. (2016), Sharkey et al. (2015), and Smith et al. (2012). The committee observed that none of these papers provided a thorough evaluation of the health effects associated with burn pit exposures, nor did they show that service members were at an increased risk of health effects associated with burn pits in particular. It did note, though, that “other hazards may be important contributors to respiratory symptoms and disease” (NASEM, 2017, p. 24). These studies were also summarized in Chapter 4. Newer Research Addressing the Health Effects of Exposure to Burn Pit Emissions This report extends the summaries and reviews presented above by considering the literature published through early 2020. One additional epidemiologic study was found that overtly factors in burn pit emissions—Rohrbeck et al. (2016)—but that study addressed only diseases of the respiratory system and signs, symptoms, and ill-defined conditions involving respiratory system and other chest symptoms in general rather than specific outcomes. The study compared diseases identified during post-deployment clinical encounters in 200 service members deployed to either Joint Base Balad (n = 163) or Bagram Airfield, Afghanistan (n = 37)—both of which had burn pits in operation during the time period of their deployments—with 200 who were never deployed. Data were derived from Defense Medical Surveillance System (DMSS) records. The investigators found that when comparing specific deployed cohorts, those at Balad had statistically significant decreased adjusted risk of signs, symptoms, and ill- defined conditions involving respiratory system and other chest symptoms compared with the nondeployed cohort. There were too few counts for an effect estimate to be calculated for Bagram Airfield. Although the estimates were adjusted for age, sex, race/ethnicity, occupation, deployment history, and history of illness prior to deployment, no information on deployment duties or specific individual behaviors, including smoking was included. Finally, as mentioned elsewhere in the chapter, investigators at the Air Force Research Laboratory (AFRL) have developed a test apparatus for examining the effects of burn pit emissions using a rat model (DelRaso et al., 2018). The apparatus consists of a 6 m high × 6 m wide × 45 m long stainless-steel tunnel with a fan at one end to simulate up to a 5-mph breeze. Materials simulating burn pit waste are burned at the inlet end of the tunnel in a manner that mimics open burn pit conditions. Preliminary results generated by the investigators attributed most of the observed effects in the experimental animals to the stress induced by testing. Additional research is under way (Mauzy, 2019) but had yet to be published when this report was completed.

196 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES Literature Regarding the Composition of Burn Pit Emissions A small literature is also available on the composition of burn pit emissions. Emissions released by burn pits are a complex mixture of various chemicals and particulates that depend on factors such as the composition of the trash burned, the accelerant used, the temperature, the ventilation, and the burn rate (Woodall et al., 2012). Some monitoring of these emissions was conducted during the time that burn pits operated in the theater. The U.S. Army Public Health Command and the Air Force Institute for Operational Health conducted a series of ambient-air sampling and screening health-risk assessments of burn pit exposures at Joint Base Balad in 2007 and again in 2009. The assessments were designed to measure the concentration of airborne pollutants released by burning at several sites on base and to detect potentially harmful inhalation exposures for personnel (APHC, 2010; CHPPM and AFIOH, 2009; Taylor et al., 2008). Even though these efforts were limited by their inability to provide information about individual exposure assessment as well as by their inability to distinguish among the contributions from particular sources (combustion engines, burn pits, dust storms, and the like), they do yield some information about the constituents and ambient levels of airborne toxicants that may have been present on bases with burn pits. A 2011 review of the monitoring efforts at Joint Base Balad conducted by a committee of the Institute of Medicine (IOM, 2011) found that • PM concentrations in ambient air were on average higher than U.S. pollution standards. PM was most likely a result of local sources (vehicle traffic, aircraft emissions) and regional sources (long-range anthropogenic sources, dust storms), although the burn pit likely made some contribution. • Polychlorinated dibenzo-p-dioxins and dibenzo-p-furans (PCDD/Fs) were detected at low concentrations. Although species associated with greater toxicity were higher than generally found in the United States or in urban environments worldwide, they were lower than levels associated with some non-military sources present in the theater. • Concentrations of volatile organic compounds (VOCs) and polycyclic aromatic hydrocarbons (PAHs) were similar to those reported in major urban areas outside the United States, with major sources being regional background, ground transportation, stationary power generation, and the airport at Joint Base Balad (IOM, 2011). Subsequent studies also noted the contribution of the Joint Base Balad burn pit to PCDD/Fs on base as well as the important role of other sources of emissions, including the airfield, as the primary source of PAHs. Other important contributors to PAH levels were aircraft, vehicle emissions, space heaters, and diesel generators (Masiol et al., 2016a,b). These observations were confined to the pollutants that were targeted by DoD and the conditions (meteoro- logical, waste stream composition, operating conditions) present at the time of the measurements. Several criteria pollutants commonly monitored in the United States and likely released by burn pits were omitted by DoD’s sampling, including sulfur dioxide, ozone, nitrogen dioxide, and carbon monoxide. Other pollutants not included in the sampling included those known to be associated with the burning of household waste (EPA, 1997, 2001; Lemieux et al., 2003, 2004), geologic material, carbon from combustion sources, metals from regional smelting activities, and other gaseous pollutants produced by combustion engines (Engelbrecht et al., 2009; IOM, 2011). Thus, the available monitoring data provide information on exposures to the major types of constituents from burn pit emissions, but they lack information on other chemicals that were likely present as well as on exposure variability over time (IOM, 2011). Other data collected as part of a monitoring program for a solid waste disposal facility at the Bagram Airfield in Afghanistan emphasize the variability of exposures associated with burn pits (Blasch et al., 2016). The facility operated a burn pit from 2005 to 2012. The investigators collected breathing zone samples, unlike the case with Joint Base Balad, but only PM and VOCs were studied. The sampling was conducted at four security locations (up to 125 meters from the burn pit) and a control location (4 km from the burn pit) during 30 12-hour shifts. Among VOCs detected, only acrolein exceeded the 1-year military exposure guideline, but benzene was detected in all samples. The range of PM concentrations varied considerably in association with airfield activity (vegetation

ADVANCING THE UNDERSTANDING OF RESPIRATORY HEALTH ISSUES 197 removal, removing mines and incendiary devices, road construction, vehicle traffic, industrial activity, air traffic). The highest recorded concentrations of environmental PM2.55 (0.615 mg/m3) occurred at the solid waste disposal facility where the burn pit and incinerators were located. High PM2.5 and PM106 concentrations were also noted at the bazaar, a highly populated site with unpaved roads and considerable vehicular traffic. The investigators thus concluded that “[t]he diversity of results support the concept of a complex environment with multiple polluting sources and changing meteorological and operational conditions” (Blasch et al., 2016, p. S38). This information is supplemented by the content of two presentations made to the committee responsible for the National Academies report (NASEM, 2017) at a May 2015 workshop. John Kolivosky provided an overview of an in-theater ambient air monitoring program (Kolivosky, 2015). Mr. Kolivosky was the project lead on a burn pit assessment conducted in the Deployment Environmental Sur- veillance Program at the Army Institute of Public Health, and he provided the committee with details on how the effort was conducted and on the data that were collected. He said that personnel would conduct site surveys to identify potential exposure to airborne hazards and collect 24-hour time-composite samples using Environmental Protection Agency methods or the equivalent. Samples were sent out of theater for analysis and later archived in the Defense Occupational and Environmental Health Readiness System–Industrial Hygiene (DOEHRS-IH). Some 20,000 samples are in the database; most of these were taken within the boundaries of bases. PM—both PM10 and PM2.5—as well as heavy metals and VOC levels were measured at various times. Mr. Kolivosky indicated that there were a number of challenges associated with operating air sampling equipment in theater that limited the ability to collect good data. Major Charlie Toth from the U.S. Air Force spoke about environmental sampling at Joint Base Balad (Toth, 2015). Major Toth focused on his knowledge of the design of the burn pit study sampling plan for the site and on personal observations from the actual collection of samples and the subsequent report. The sampling plan was a joint effort with the Army CHPPM and Air Force Institute for Operational Health. The goal was to quantify the worst-case effects of exposures to the open burn pits. The intent of investigators was to gather this information while waste incinerators were still in place and the exposure was still comparable to what the exposed population had experienced. Major Toth described his experience as an environmental engineer tasked with collecting samples near the base and creating the resulting report published from the data gathered (CHPPM and AFIOH, 2009). Between January and May 2007, samples were collected to assess the levels of dioxins, furans, PAHs, VOCs, and PM10 particulates. Major Toth said he recalled seeing during his time in theater a number of types of items in burn pits, including plastics, metal/aluminum cans, rubber, chemicals such as paints and solvents, petroleum, oil, lubricant products, munitions, unexploded ordnance, wood waste, and incomplete combustion byproducts, with jet fuel (JP-8) being used as the accelerant. The report summarizing this work noted that the actual number of final samples collected was relatively small and that 15% of the samples were rejected because of damage from shipping or failed pumps. The report’s findings did not include input or verification from members of the team involved in the collection of data, which led, in Major Toth’s view, to flaws and misinterpretation of information. Since these reports, there has been scant additional information published on burn pit emissions. The com- mittee identified three studies that addressed the issue. Dominguez et al. (2018) characterized emissions from the burning of meals, ready-to-eat (MRE) packaging typically found at forward operating bases in the theater. It reported that PM2.5 constituted the vast majority of these emissions. VOCs and PAHs were also detected, along with relatively small amounts of PCDD/F congeners. Xia et al. (2016) conducted a pilot study that analyzed PAHs and PCDD/Fs in pre- and post-deployment serum samples obtained from 200 service members deployed to Iraq or Afghanistan plus an equivalent number of nondeployed controls. Many of the chemicals were found in the serum of both the deployed and the nondeployed subjects. For PAHs, naphthalene7 was found in 83% of the samples and was statistically different in post-deployment versus pre-deployment serum, as were several PCDD/ Fs. The investigators concluded that the study showed that such measurements had the potential of being used as exposure markers. Subsequently, M. R. Smith et al. (2019c) used high-resolution metabolomics to test for changes 5  PM refers to particulate matter with a diameter less than 2.5 microns. 2.5 6  PM refers to particulate matter with a diameter less than 10 microns. 10 7  Naphthalene is generated by biomass burning and gasoline and oil combustion. It was also used as a reptilicide in the theater.

198 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES in the levels of 271 environmental chemicals in post-deployment serum samples versus pre-deployment levels and in matched controls stationed in the United States. Of that list, 153 chemicals (56%) were detected, with non- significant increases in pesticide exposures found in the deployed group relative to the nondeployed. No increases in chemicals related to burn pits were reported. Observations Regarding the Hazards Associated with Burn Pit Exposures The committee’s literature review identified relatively little evidence addressing how burn pit exposures may result in adverse respiratory health outcomes, and what epidemiologic literature there is has not found an associa- tion. This is in contrast to the much larger literature regarding exposure to airborne hazards in general and to PM in particular. Concern over burn pit exposures is understandable, given their prominence as a source of smoke, vapors, gases, and fumes in military facilities where large numbers of service members were present as well as the known toxic effects of the byproducts of combustion of the materials that were burned in them. To date, though—other than the self-reported airborne exposures and health information collected as part of such efforts as the Millennium Cohort Study and the Airborne Hazards and Open Burn Pit Registry—there have been no large-scale systematic data collection or maintenance efforts focused on the effects of exposure to burn pit emissions.8 There are means, though, to gain a better understanding of this issue. As part of its Statement of Task, the committee responsible for the 2011 Institute of Medicine report Long-Term Health Consequences of Exposure to Burn Pits in Iraq and Afghanistan was asked to assist VA with the design of an epidemiologic study of the poten- tial long-term health effects of exposure to burn pit emissions. The committee developed a detailed research plan that focused on personnel deployed to Joint Base Balad in Iraq but also encompassed veterans exposed to burn pit emissions at any U.S. military base with operating burn pits. The committee that produced that report recommended that a cohort study of the long-term health effects of exposure to burn pits (evaluated prospectively) be conducted using retrospective estimates of exposure to burn pit emissions in military personnel deployed to the theater. The observation period for health effects would begin retrospectively at first deployment and continue after active-duty service was completed. The committee noted that to determine the incidence of chronic diseases or cancers with long latency, study subjects would need to be followed for many years. That committee recommended that pilot studies be conducted to address issues of statistical power and to develop design features for specific health outcomes, and it stated that once a prospective cohort infrastructure had been established, multiple health outcomes could be studied in the cohort over time. The committee suggested that intermediate outcomes on the pathway to the development of chronic diseases could be studied in a serial manner, offering the example of serial spirometry being used to detect excessive rates of decline in lung function before a diagnosis of chronic obstructive pulmonary disease (COPD). This committee endorses the approach identified by the committee for Long-Term Health Consequences of Exposure to Burn Pits in Iraq and Afghanistan as a template for comprehensively studying respiratory health outcomes in theater veterans exposed to burn pits but notes that nearly 10 years have passed since the develop- ment of that report and that refinements in and an expansion of its protocols would be appropriate. The range of exposures examined should not be limited to burn pit emissions but instead be enlarged to include all airborne contaminants for which measurements or exposure surrogates are available. This committee notes that those deployed are often at the peak of their lung function, which occurs in their early 20s, and that exposures related to deployment, including burn pits, may increase the rate of decline in lung function over time and increase the risk for conditions such as COPD. Longitudinal studies that include baseline and lung function assessment over time as well as imaging and other respiratory assessment could be used to address this question. This chapter also cites advances in retrospective exposure assessment via biomarkers and through the analysis of historic satellite observational data, the latter of which might be particularly useful for veterans who served outside of large-scale bases like Joint Base Balad, where air sampling and other exposure information would have been more limited. 8  Very limited in-theater air pollution data-gathering efforts have generated information that would aid in studies of those who served in the same place and at the same time as measurements were made.

ADVANCING THE UNDERSTANDING OF RESPIRATORY HEALTH ISSUES 199 KNOWLEDGE GAPS Chapter 4 presents the committee’s critique of the epidemiologic literature on respiratory health outcomes associated with in-theater exposures of active and former military personnel. This includes their judgments on the strengths and weaknesses of the current information base, notably, the several outcomes for which there was inadequate or insufficient information from which to draw a conclusion. Here the committee expands on that analysis by taking a broader view: specifically, identifying the common elements that limit our understanding of the possible nexus between in-theater airborne exposures and adverse respiratory health outcomes. Recommenda- tions for addressing these gaps—including research that could be conducted, technologies that could brought to bear, and organizations that VA could partner with to accomplish the work—appear in later sections of the chapter. This and the following sections of this chapter discuss but do not present comprehensive assessments of the scientific literature regarding the many potential avenues for future research that VA could conduct or foster—an undertaking outside the committee’s Statement of Task. Gaps in Knowledge Concerning Adverse Respiratory Health Outcomes in Theater Veterans Although there have been a number of studies of respiratory health outcomes in veterans of the Southwest Asia conflicts, the committee found that there was inadequate or insufficient information from which to draw a conclusion about the association between in-theater airborne exposures and several outcomes. The reasons for these findings, as noted in Chapter 4, varied. One underlying reason was that crucial data may not have been available, as would be the case if investigators were using information derived from an administrative data set. The com- mittee notes, for example, that several studies failed to adequately account for cigarette smoking—a known cause of respiratory health problems—in their analyses of outcomes. Another is that some health outcomes, such as pulmonary fibrosis, occur so infrequently that it can be difficult to discern empirically whether the incidence in a study population is different from what would otherwise be expected. This can be the result of a lack of knowledge concerning the background rate or the effort and expense entailed in conducting an adequately powered study. For other outcomes, such as cough, the challenge is that they occur frequently and have many potential underlying causes, making it more difficult to study the influence of any single factor without good exposure information, which the committee lacked. For constrictive bronchiolitis, an outcome that the committee was asked to give special attention to, there is an open question as to whether the diagnostic criteria for the disease are being correctly and consistently applied (Furlow, 2020; Garshick et al., 2019). And, finally, there are circumstances where a disease may not manifest for several years after an adverse exposure takes place, meaning that insufficient time may have passed since an exposure in the theater for that outcome to be observed in an epidemiologic study. Gaps in Knowledge Concerning In-Theater Airborne Exposures The committee enumerated a number of airborne exposures that could have influenced respiratory health out- comes in the veterans of the Southwest Asia conflicts. These include environmental and occupational exposures as well as those resulting from personal behavior and the circumstances of being deployed in the Southwest Asia theater. Exposure characterization is a pervasive challenge in studies of the effects of exposures on military person- nel. Basic information is often lacking on who was exposed, what they were exposed to where and when, at what level, over what time period, and with what frequency. A small number of measurements were taken in various theater locations at specific times. For example, the U.S. Army CHPPM performed ambient air PM monitoring for 5 days in Sykes, Iraq, in August 2008 (CHPPM, 2008) and for 13 days in Kandahar, Afghanistan, in June 2009 (CHPPM, 2009). Longer-term monitoring data for a number of theater locations are available in periodic occupational and environmental monitoring summary (POEMS) files maintained by the Army Public Health Center (APHC, 2018). Results from many of these sampling exercises are located in the DOEHRS-IH database (DHA, 2018). A 2019 review of these POEMS, though, con- cluded that “inconsistent collection, assessment, and presentation of available data seriously weakens the potential utility of the POEMS files as the primary source of information on toxic exposures” (Williams and Fahey, 2019). Data on air pollutant levels in-theater or personal exposures to specific air contaminants are generally lacking.

200 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES Exposure proxies, such as a person’s location and proximity to sources at specific times, are sometimes available, but even these data can be difficult to obtain, and self-reports—especially those gathered long after the putative exposure—may be subject to recall bias. Furthermore, the POEMS available are those that have been approved for public release and cleared for open publication.9 Past reports in the Gulf War and Health series have raised concern over the lack of good exposure informa- tion on depleted uranium (IOM, 2000b, 2008); insecticides and solvents (IOM, 2003); and fuels, combustion products, and propellants (IOM, 2005), among other in-theater hazards. As Volume 10 of the series states: “[t]he lack of specific individual exposure information is not unexpected in wartime situations, but it nonetheless limits the ability to draw conclusions about observed health effects” (NASEM, 2016b, p. 240). An additional complica- tion arises with hazards such as burn pit emissions, which were highly variable over time, depending on which m ­ aterials were burned and at what temperature combustion occurred (IOM, 2011; NASEM, 2017). Burn pits were later supplemented with or replaced by incinerators at some larger installations, which further complicates the evaluation of exposures over time, given the lack of emissions monitoring. These circumstances are illustrative of the gaps in information that represent a major barrier to the analysis of potential health effects. Gaps in Knowledge Concerning the Biologic and Toxicologic Effects of In-Theater Airborne Exposures Concomitant with the lack of information on the characteristics and levels of in-theater airborne exposures are the gaps in knowledge concerning the biologic and toxicologic effects of those exposures. The com­ ittee’s m review of the literature identified three major themes that characterize these gaps. All are again pervasive in envi- ronmental health studies. The first gap is the absence of information on mixtures. This is of concern because interactions among expo- sures may unpredictably result in increased or decreased effects relative to those of individual components, greatly complicating the assessment of risk. Indeed, the committee responsible for the National Academies report Gulf War and Health: Volume 11: Generational Health Effects of Serving in the Gulf War (NASEM, 2018b) concluded that the lack of information on exposures and toxicologic information related to the complex chemical mixtures often encountered during environmental and occupational exposures precluded an adequate assessment of the effects of deployment exposures. A second knowledge gap regarding effects assessment is the lack of good animal models for in-theater expo- sures. Such models permit a greater understanding of how particular exposures may result in biologic changes, manifestations of signs and symptoms, and specific diseases. Studies have been done with rats and Southwest Asia dust (Porter et al., 2015; Szema et al., 2014; Taylor et al., 2013; Wilfong et al., 2011); cats (Moeller et al., 1994) and hamsters (Brain et al., 1998) and smoke from the Kuwait oil-well fires; and mice and pesticides used during the 1990–1991 conflict (Repine et al., 2016). A few investigators have also directly examined the toxicity of particular hazards experienced by military personnel when deployed to Southwest Asia. Some have focused on PM (Dorman et al., 2012; Porter et al., 2015). In addition, J. P. Smith et al. (2019) examined potentially toxic elements in the fine fraction of soils from Iraq and Kuwait, which the authors indicate could become suspended during wind storms. Others have performed analyses of emissions from the plastics, paper, food, wood, cloth- ing, and Styrofoam materials most commonly found in military operations—singularly (Pan et al., 2013) and in mixtures (Aurell et al., 2012; Dominguez et al., 2018; Woodall et al., 2012)—and characterized their properties. Investigators at AFRL have developed a model that shows great promise for more completely examining the effects of in-theater inhalation exposure by using simulated burn pit emissions mixed with desert sand to study pulmonary morbidity in rats (DelRaso et al., 2018; Mauzy, 2019). DelRaso et al. (2018) reported on changes in urine metabolites, microRNA (miRNA) expression profiles, and related pathways in rats exposed to sand and burn pit emissions. Paired analysis revealed minor effects due to exposures to sand and burn pit emissions, but the majority of the observed changes were attributed to stress induced by the experimental protocols. Due to 9  See https://www.esd.whs.mil/Portals/54/Documents/DD/issuances/dodi/523009p_1.pdf (accessed July 1, 2020). DoD indicates that release is limited only as ­ ecessary to safeguard information requiring protection in the interest of national security or other legitimate governmental n interest.

ADVANCING THE UNDERSTANDING OF RESPIRATORY HEALTH ISSUES 201 logistic limitations, these exposures were conducted sequentially (sand followed by burn pit emissions), though, and thus do not reflect the real-world exposure scenarios that occurred in-theater. Camilla Mauzy (2019), in an October 2019 presentation before the committee, outlined a number of additional research projects being carried out by AFRL investigators that have not yet been published. These include studies of blood proteomics (including potential biomarkers) and the lung microbiome in exposed animals. The committee encourages AFRL to facilitate the publication of this work in the open literature so that it can reach the broader research community. The third knowledge gap identified by the committee regards differences in vulnerability and ­ usceptibility10 s to respiratory health problems arising from toxic airborne exposures in military populations. As Falvo et al. (2015) note, while there is a robust literature on the effects of exposure to PM and other air pollutants commonly encountered in the Southwest Asia theater, a knowledge gap exists because “[i]ndividual susceptibility factors in deployed military personnel have not been thoroughly studied in the contexts of airborne hazards exposure” (p. 119). These individual factors include genetic pre-disposition, underlying health issues, social determinants (such as socioeconomic status and access to health care), prior exposures, and the multiple stressors present in a military environment—not just chemical, biologic, radiologic, nuclear, and high-yield explosives exposure, but also combat, noise, altered work/rest patterns, and disruptions to family and other social support systems. Biologic and toxicologic research published to date has thus made a start on informing questions related to the effects of airborne exposures but has not covered all of the issues of interest—in particular, in the study of clinically relevant endpoints. Analyses of tissue burdens, changes in organ systems, and pathologic and histologic alterations are needed to better relate laboratory results to health effects observed in deployed personnel. Other Gaps in Knowledge The lack of good biomarkers of exposure, effect, and susceptibility11 to in-theater environmental insults is a knowledge gap that has received considerable attention of late, including a long-term DoD study—the Military Biomarkers Research Study (Mallon et al., 2019)—and a 2018 National Academies workshop (NASEM, 2018a). These markers were also addressed by several speakers who presented at the workshop that the committee con- vened in October 2019. The following are common themes identified by these sources: • Biomarkers are a new and potentially powerful means of overcoming the lack of specific information on personal exposures in military environments and how they affect deployed personnel. • Technologic advances allow the identification of candidate biomarkers with far greater speed and at far lower cost than was previously possible. • Extant collections of biospecimens such as the DoD Serum Repository (DoDSR) and materials collected as part of epidemiologic investigations such as the Millennium Cohort Study are useful in identifying candidate biomarkers. • Recent advances in research indicate that there are biomarkers associated with service in the Southwest Asia theater and specific exposures found in that theater. Biomarkers research is addressed in greater detail later in the chapter. Additional gaps—referenced throughout Chapter 4 and this chapter—relate to issues that limit almost all epi- demiologic studies of the effects of occupational and environmental exposures in service members and veterans. These include the reliance on self-reports of exposure and outcomes, the lack of objective tests and measures for 10  Vulnerability in this context refers to an individual at higher risk due to environmental or personal factors, such as from occupational exposures, while susceptibility refers to intrinsic biological factors that can increase the health risk of an individual at a given exposure level (Portier et al., 2013). 11  A biomarker of exposure is “an exogenous substance or its metabolite or the product of an interaction between a xenobiotic agent and some target molecule or cell that is measured in a compartment within an organism.” A biomarker of effect is “a measurable biochemical, physiologic, or other alteration within an organism that, depending on magnitude can be recognized as an established or potential health im- pairment or disease.” A biomarker of susceptibility is “an indicator of an inherent or acquired limitation of an organism’s ability to respond to the challenge of exposure to a specific xenobiotic substance” (NRC, 1989, p. 17).

202 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES these exposures and outcomes, the use of deployment as a surrogate for exposure, the number and variety of con- founding factors that might influence the outcome under study, and the time that has elapsed between deployment or exposure and evaluation of health outcomes. RESEARCH THAT COULD FEASIBLY BE CONDUCTED Given the knowledge gaps identified above, the committee addressed what research could feasibly be con- ducted to inform these issues and generate answers. In tackling this element of the Statement of Task, it considered not just research that would directly help to answer outstanding questions but also initiatives that would generate data that could be used in the future to move the field forward. Research Addressing Constrictive Bronchiolitis and Excess Mortality In the course of its work, the committee identified a number of opportunities to advance knowledge on issues related to respiratory health outcomes related to airborne exposures in Southwest Asia theater veterans. Two outcomes that were highlighted in its Statement of Task—constrictive bronchiolitis and excess mortality from respiratory-related causes—are discussed below. Constrictive Bronchiolitis Constrictive bronchiolitis includes several small airway diseases that are defined by the presence of bronchiolar ­ inflammation, fibrosis, or both. The pathological criteria include “a pattern of injury characterized by subepithelial scarring resulting in narrowing or obliteration of the bronchioles, without the presence of luminal plugs” (Garshick et al., 2019). The interpretation of lung biopsies for the presence of constrictive bronchiolitis has proven to be controversial, leading to uncertainty over the diagnoses of veterans exposed to airborne agents encountered in the Southwest Asia theater. Given the interest surrounding the question of whether in-theater exposures may be responsible for an increase in the prevalence of constrictive bronchiolitis in veterans of the Southwest Asia conflicts, the committee concludes that actions to resolve this issue should be given a high priority by VA. The central uncertainty at this time (early 2020) is whether case reports of the disease in the population (Garshick et al., 2019; Gutor et al., 2019; King et al., 2011; Madar et al., 2017; Weiler et al., 2018) indicate that it is occurring with greater frequency than would be expected. Among the suggestions offered by the American Thoracic Society workshop participants who addressed this issue in 2018 was the call for [m]ore consistent characterization of specific histologic abnormalities, including the prevalence of constrictive bronchiolitis and other small airway abnormalities, established through review of biopsy material using standardized criteria comparable across studies and delineating the relationship of such pathologic abnormalities with PM and other exposures. (Garshick et al., 2019, pp. e-12–e-13) The committee concurs with this observation. Much of the current debate regarding the prevalence of constric- tive bronchiolitis is the result of uncertainty and disagreement over the interpretation of the pathologic findings in symptomatic individuals. In order to better manage these circumstances, the committee recommends that VA establish an expert panel to advise it on issues related to the diagnosis of constrictive bronchiolitis in vet- erans and its possible relationship to military service. This panel should be external to VA and should include a range of expertise in areas such as pulmonary medicine, toxicology, epidemiology, exposure assessment, and radiology but with the primary membership consisting of experienced pulmonary pathologists. The panel should also include veteran representation. The expert advisory panel would be charged with developing specific guidelines for VA’s evaluation of symptomatic Southwest Asia theater–deployed veterans in whom the differential diagnosis includes constrictive bronchiolitis. Its short-term and longer-term tasks would include the following:

ADVANCING THE UNDERSTANDING OF RESPIRATORY HEALTH ISSUES 203 • Determination of the adequacy of various lung biopsy approaches for the diagnosis of constrictive bronchiolitis and recommendations for best practices. • Development of recommendations for consistently processing, handling, and storing lung biopsy materials. • Creation of consistent histologic/pathologic criteria to be used for confirming a diagnosis of constrictive bronchiolitis in theater veterans with suspected cases who present at a VA facility or who apply for disability compensation for the disease. • Review—by the pathology working group within the panel—of biopsy slides from cases in which the issue of a diagnosis of constrictive bronchiolitis related to service has been raised. This review should not be limited to controversial cases but instead should be applied to all such cases that fall under VA’s areas of responsibility. The working group should be charged with providing a written summary report of each case in a timely manner. • Establishment of criteria for the evidence base for determining whether an association exists between a veteran’s military service and constrictive bronchiolitis, including the types and sources of information that could be considered. • Recommendations for the research that would help resolve outstanding questions regarding constrictive bronchiolitis in veterans. • Revision of the guidelines as new evidence becomes available. The committee notes that it is unclear how many cases of constrictive bronchiolitis might be subject to review under this proposal and that the expert panel may need to adjust the criteria for reviewing cases in order to estab- lish a realistic workload within the confines of achieving these goals. It further recognizes that the creation of this advisory committee and its role in peer review is not without controversy or cost, but it believes that it is critical to ensure that VA has a consistent approach in establishing or denying a diagnosis and evaluating its possible service connection. It should also reassure veterans that they are receiving a fair review that uses the best science. The committee also acknowledges that there are other approaches that could be used to institute a peer-review process for constrictive bronchiolitis that would have their own advantages and disadvantages. No matter which approach VA ultimately chooses, it must have as its foundational principle that all information and actions be documented and—to the extent that protection of privacy and personally identifiable information allows—be made public so that the evidence base used to make decisions on possible links between military service and constric- tive bronchiolitis is transparent and the decisions are uniformly reached. The determination of the prevalence of ­ this condition through epidemiologic studies must await the establishment of an agreed-upon selection of clinical criteria for biopsy and agreed-upon pathologic diagnostic criteria. Excess Respiratory Mortality The committee’s review of the literature found that the last general mortality study of post-9/11 veterans who had been deployed to the theater was generated using data from 2011 (Bollinger et al., 2015). This analysis examined all-cause mortality only and did not present information on specific causes, such as respiratory diseases. The most recently published study of 1990–1991 Gulf War veterans, which did include mortality from COPD or from respiratory system diseases in general, used 2004 as its cutoff date (Barth et al., 2016). An information gap thus exists—one that is important to address in order to identify outcomes that warrant more intense study or surveillance of this population. Fortunately, data are readily available to fill this gap. The Mortality Data Repository, a joint VA/DoD effort, contains all-cause mortality information for veterans, service members, and Veterans Health Administration users obtained from the National Center for Health Statistics’ National Death Index, starting in 1979 (VA, n.d.). Other sources include veteran-specific resources, such as the Beneficiary Identification and Records Locator System death files, VA/Centers for Medicare & Medicaid Services Medicare vital status files, VA facilities patient treat- ment files, and the VA Corporate Data Warehouse,12 as well as general mortality information collections, such as the Social Security Administration Death Master File and state death records (VA, 2019). 12  The Corporate Data Warehouse is a centralized source of digitized Veterans Health Administration information (https://www.hsrd.research. va.gov/for_researchers/vinci/cdw.cfm [accessed July 1, 2020]).

204 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES Future mortality studies need to be based on internal analyses that compare veterans exposed to higher and lower levels of airborne agents rather than analyses that compare all veterans to the general population. This in turn requires that a retrospective exposure assessment be a necessary component of any future mortality study if it is to produce useful estimates of exposure-related mortality risk. An informative new study to determine whether there is excess mortality in deployed veterans should also consider a number of parameters. These include not just the cause of death and contributing causes of death but also the following: • Other underlying health conditions that might not be listed as a cause or contributing cause of death but that might confound an association • Exposure information from biomarker test results, contemporaneous measurements, retrospective analyses, or self-reports • The number of deployments • The timeframes of deployments (not just the dates and number of days or months, but other potentially influential factors such as the season) and of total military service • As much granularity regarding location in theater as possible, including service at sites with known hazardous airborne exposures • Demographic and socioeconomic characteristics (age, race/ethnicity, sex, education, family income, and the like) • Military service information that might influence exposures such as rank and occupational specialty • Potentially confounding personal characteristics such as alcohol use and smoking history Changes of effect measurements should be considered in light of baseline physiologic measures of pulmonary function, blood pressure, or existing health conditions (if available) as well as of the other factors mentioned above. Given this, the committee recommends that VA conduct or sponsor an updated analysis of total and respiratory disease mortality in Southwest Asia theater veterans. One means to accomplish this would be to perform an update of the analyses conducted by earlier investigators, using the cohorts they identified and extend- ing the time period to the extent that the data allow. In addition to adding cause-specific mortality for respiratory outcomes, it would be useful to include metrics of airborne exposures, the location and timing of deployments, mili- tary occupation, service branch, pre-existing health status, and personal information (including smoking history) to the extent available. The study should perform internal comparisons between more and less exposed veterans ­ in order to permit a better evaluation of the effect of in-theater exposures. Although it is worth replicating the calculations performed in the 2011 study for comparison purposes, the study should also apply survival methods, such as Cox proportional hazards models, to estimate hazard ratios as the measures of association between specific mortality outcomes and exposure to respiratory hazards. The mortality outcomes of interest should include both respiratory cancers and nonmalignant respiratory outcomes, such as asthma and COPD, as well as a calculation of all causes of death combined. Attention, however, should be directed only to outcomes where sufficient time has elapsed since exposure to allow for disease latency and survival. In light of the literature on susceptible popula- tions, effect modification should also be considered to examine whether the exposure–response relationships in these populations vary by education, income, rank, or other socioeconomic factors, as well as by race/ethnicity, sex, age, and smoking history. Other Outcomes for Which There Is Currently Inadequate or Insufficient Information As already noted, the committee’s review of epidemiologic literature regarding associations between South- west Asia theater exposures and respiratory health outcomes identified several outcomes for which there is cur- rently inadequate or insufficient information on which to draw any conclusion. For some of these, it is unlikely that further progress will be made from observational studies, such as in circumstances where the outcome is too rare to allow for a meaningful analysis of the effect of in-theater exposures. However, for other outcomes, such as asthma, chronic bronchitis or COPD, and upper airway conditions (sinusitis, for example), future research has the potential to increase our knowledge concerning whether in-theater exposures and outcomes are associated. An

ADVANCING THE UNDERSTANDING OF RESPIRATORY HEALTH ISSUES 205 important question to answer in this regard is whether research that builds on existing studies would serve this purpose or whether new studies are required. It would likely be more efficient to build onto existing efforts using cohorts such as STAMPEDE or the Millennium Cohort Study. However, in light of the limitations of these cohorts (outlined below), there is a risk that supplementing them with new data will not in fact result in any meaningfully higher level of confidence in the findings. In order to resolve this question, it is useful to identify some feasible ways to supplement existing studies to help provide a fuller picture of how they might be improved and to provide a better basis for addressing the health outcomes of interest. The following are some possible additions: • Improved spatio-temporal estimates of ambient air pollution exposures using, for example, the advances in retrospective exposure assessment identified in this chapter. • More detailed information on the study subjects’ personal characteristics (smoking behavior, for example) and their deployments (location, time period, number of deployments) obtained through medical records, administrative data, and other extant sources. • Biospecimen data. • Supplementary health status and outcomes data (imaging, physiologic parameters, and the like). The limitations of the existing studies evaluated by the committee include poor rates of participation, self- selected participant populations, and self-reported health outcomes data. Poor participation rates raise the possibility of selection bias, most likely creating or strengthening associations between exposures and outcomes when such associations do not truly exist. Other studies of U.S. military and veteran populations have made use of administrative data that for the most part do not rely on self-reports, such as data from the DoD Manpower Data Center (which includes a roster of all military personnel and deployments), the Armed Forces Health Surveillance Branch (which contains deployment information), and DMSS (data on medical encounters). Sources such as the National Death Index, the Armed Forces Medical Examiner System, VA, and the Social Security Administration have also been used to provide supple- mental information. Although such administrative data do get around the drawbacks of self-reports, they present a different limitation: they typically do not contain adequate information on important confounding ­ ovariates that c are desirable to include to reduce uncertainty in these analyses. As already noted, a characteristic that is common to all of the studies reviewed by the committee is the use of relatively crude estimates of exposure. Typically, deployment status (deployed versus nondeployed) is used, sometimes refined to include features such as the duration and number of deployments. In many circumstances, exposures are self-reported, raising the strong possibility of information bias that may be differential among persons who have the outcome of interest versus those who do not. The available information suggests that the most feasible and efficient way of supplementing existing cohorts—the way that would have the greatest likelihood of increasing confidence in the study findings— would be to apply spatio-temporal model predictions of ambient air pollution concentrations during periods of deployment, provided that information on deployment location is available. Such an effort would reduce the measurement error and possible information bias inherent in using crude exposure measures that assign the same exposure to all deployed personnel, when there is a wide range of exposure intensity across the deployed population. On the other hand, supplementing existing cohort data with data from biorepositories or additional outcome measurements or records would be less likely to result in any meaningful progress in overcoming the limitations of these cohorts and moving the level of confidence in the evidence from where it is currently. Biorepository specimens that were not collected as part of a systematic research study may be of ­ varying and uncertain quality13 (IOM, 2012), and outcome measures other than those directly obtained by health p ­ rofessionals from a population that is representative of the individuals who served in theater will suffer from the same problems as the existing information. 13  An exception to this would be specimens obtained for the DoD Serum Repository (DoD, 2020b), which are subject to uniform and rigor- ous collection protocols.

206 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES Some suggestions for designing a new generation of studies that would deliver more definitive findings are detailed in this chapter, as well as a systematic approach to evaluating suspected cases of constrictive bronchiolitis. In addition, a need was identified for continuing and new experimental studies using appropriate animal models and relevant exposure scenarios. There are currently scant toxicologic data that serve this purpose. Such studies would serve the primary purpose of assessing the plausibility of the associations under study by observational studies and thereby potentially adding to the evidence base as well as providing insights into the pathobiologic mecha- nisms underlying the effects of the various exposures encountered in the theater. Ongoing and new experimental toxicology studies using appropriate animal models and relevant exposure scenarios should also be encouraged. Outcomes in Susceptible Subpopulations As previously noted, almost no information exists on whether particular subpopulations may be at greater risk for respiratory health problems associated with Southwest Asia theater exposures. One paper that did address this topic—Dursa et al. (2019)—examined health outcomes in 1,572 female and 6,532 male veterans of the 1990–1991 Gulf War. The investigators found that deployed female veterans were statistically significantly more likely to report a diagnosis of asthma than deployed male veterans (odds ratio [OR] = 1.82, 95%CI 1.44–2.29), adjusted for age, race, service branch, and unit component. Self-reports of COPD were roughly equal in the cohorts, adjusted for the same factors as asthma (OR = 1.08, 95%CI 0.80–1.36). The committee believes that such work is important to gaining a more complete understanding of the effects of service in the theater. It observes that some analyses of this sort should be possible with already gathered data from the epidemiologic studies reviewed by the com- mittee and that more could be done in the future as validated biomarker and other information becomes available and as the time since exposure increases (which may allow for outcomes with long latency periods to manifest). Veterans with asthma have also been identified as a potentially susceptible population for respiratory disorders resulting from deployment-related airborne exposures (IOM, 2011). There has been an increase in prevalence of individuals with asthma who are under VA care (Pugh et al., 2016), underscoring the importance of studying this subgroup. Studies investigating the effect of airborne exposures on those with existing asthma require it to be characterized via such parameters as lung function, airways hyperresponsiveness, and clinical asthma status at baseline and post-deployment. A long-term longitudinal follow-up of such a population would provide the ability to study the effect of exposures on the disease course. Changes over time should be analyzed with appropriate statistical methods that quantify within-person effects. Inclusion of biomarkers that provide insight on the immune response to environmental exposures would strengthen future studies. Generally speaking, future studies of theater veterans need to better evaluate how factors such as race, gender, occupation or operational duties, diet, and the like modify the effects of airborne exposures, which would allow the identification of susceptible subpopulations. In light of the new paradigm for occupational safety and health being promoted by the National Institute for Occupational Safety and Health (Chari et al., 2018), studies of military health should consider work-related environmental, organizational, and psychosocial factors that affect health and well-being as well as modifiers of military exposures to airborne contaminants. In contrast with previous studies of military as well as other occupational groups, Bollinger et al. (2015) found evidence suggesting that veterans of the Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn conflicts were less healthy than the general U.S. population. Although respiratory outcomes were not the focus of that study, the results provide a context for evaluating such outcomes. Research suggests that low socio- economic status increases susceptibility to the respiratory and cardiovascular health effects of air pollution (Chi et al., 2016; Hooper and Kaufman, 2018; O’Neil et al., 2003), and it is plausible that respiratory effects associated with effect modification also exist (Keidel et al., 2019). Those who use VA medical services may be particularly vulnerable. Meffert et al. (2019) found that those individuals have a substantially elevated health burden compared with other veterans, perhaps as a result of their lower household incomes and longer service in the military and in combat than those who do not use VA services. Taken altogether, the literature supports the need to more fully examine effect modification in studies of theater veterans’ health. The committee has no specific recommendation in this regard but notes that this is an under- researched area that has the potential to yield a more complete understanding of the determinants of respiratory health outcomes.

ADVANCING THE UNDERSTANDING OF RESPIRATORY HEALTH ISSUES 207 Other Research Opportunities for Examining Respiratory Health Outcomes Several research opportunities exist for expanding on the currently available epidemiologic literature. These include improved consideration of confounders and effect modifiers, such as smoking; using information avail- able from biorepositories to supplement exposure and outcome information; and using integrated health records when possible. Accounting for Smoking More Comprehensively  Given the well-established association between smoking and adverse respiratory health outcomes, it is remarkable that there are studies of these outcomes that do not con- trol for smoking or that control for it in an incomplete manner. Rohrbeck et al. (2016), for example, acknowledge that the lack of individual-level smoking data is a limitation of their study. Others note behavioral choices, such as starting or restarting smoking during deployment, that could complicate analyses (Brown, 2010; Sanders et al., 2005). Smoking can confound the relationship between service and respiratory disease or it may be an effect modifier. In either case, incorrectly accounting for it (e.g., failing to factor that current smoking is less common among those with lung cancer who smoked in the past) may lead to a biased estimate. Conceptual models, such as directed acyclic graphs or marginal structural models, can be used in such circumstances to ensure that smoking is accounted for properly in the analysis. It is also important to keep in mind that smoking—or any covariate—will only be a confounder in any particular study if it is associated with the exposure metric as well as with the outcome (if, for example, veterans who were exposed to higher levels of airborne hazards in theater also smoked more). Furthermore, the committee did not identify any study of theater veterans that measured e-cigarette use, a relatively new and growing exposure that is raising health concerns (Lin et al., 2019). When possible, future studies should account for all forms of smoking—tobacco and otherwise—in order to properly study respiratory health outcomes. Finally, the committee notes that research on the use of biomarkers for smoking is evolving and will present opportunities for more complete retrospective exposure assessment in the future (Chang et al., 2017). Using Military Biorepository Information in Epidemiologic Studies  Epidemiologic studies of respiratory health effects of airborne hazards exposures in the Southwest Asia theater most often rely on qualitative prox- ies for exposure, such as deployment status (deployed versus nondeployed) or time spent within the theater. Having multiple, independent sources of exposure information would enhance the ability of investigators to retrospectively assess the effect of airborne contaminants by military personnel. As detailed in the “Organi- zations That VA Might Partner with to Address Knowledge Gaps” section later in this chapter, one largely untapped source of such information is the material already collected and stored in biorepositories maintained by or affiliated with DoD. One example is the DoDSR, a collection of 62 million sera samples from more than 10 million service members from all branches of the military that were collected at induction and then every 2 years while on active duty, as well as before and after deployment (DoD, 2020b). The serum stored in the DoDSR is used for HIV screening and to conduct epidemiologic studies and inform health policy. It may thus also serve as a supplemental means to identify chemical compounds and molecular changes (e.g., those revealed by genomic, proteomic, or metabolomic analyses) associated with various environmental exposures (Moore et al., 2010; Perdue et al., 2015; Rubertone and Brundage, 2002). To be clear, there are limitations to the utility of some of these specimens, and logistic obstacles and consent considerations to be factored into the use of others,14 but these are surmountable challenges. Greater use and easier research access to military biorepositories would allow for the evaluation of longitudinal changes in exposure to specific contaminants in targeted analysis as well as to exposures to mixtures using exposomic analysis. Good nested case–control study designs will be crucial in making best use of the materials, though. Linking the results of analyses of biobanked samples to data on service members and their tour of duty, demographics, and lifestyle choices (including smoking histories prior to and during service) data, where available, would facilitate assessments of determinants of exposure, which could in turn be used to evaluate the health effects of that exposure and to develop strategies for exposure mitigation. 14  A 2012 National Academies report addresses these challenges as they relate to report future uses of the specimens held by DoD’s Joint Pathology Center biorepository (IOM, 2012).

208 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES Biobank measurements could also support investigations of the impact of military exposure on intermediate endpoints—identified via biologic pathways of disease—through metabolomics, transcriptomics, and proteomics. Importantly, high-throughput pipelines that accommodate multi-omics analyses are already well established in universities and federal agencies, for example, through the National Institute of Environmental Health Sciences (NIEHS) Human Health Exposure Analysis Resource program (NIH, 2020a) and their extramurally funded Envi- ronmental Health Sciences Core Centers (NIH, 2020b). Results from such analyses could be combined with those from toxicologic biomarker studies to extend their utility. The utility of adding information derived from existing biorepository collections to new analyses of health outcomes in veteran populations has been demonstrated in studies of Vietnam veterans. For example, ­biospecimens from the Air Force Health Study—originally collected in the 1970s through early 2000s—were later used to examine the prevalence of monoclonal gammopathy of undetermined significance (Landgren et al., 2015; Wang et al., 2020) and the association of serum paraoxonase 1 activity and concentration with the development of type 2 diabetes mellitus (Crow et al., 2018). There would also be merit in expanding these biorepository resources to include routine collection of media such as urine, dried blood spots, or nasal and buccal swabs because these would yield information not available from the more commonly stored specimens: serum, whole blood, and tissue. Given the potential costs of such an expansion, a reasonable first step might be a pilot program that would collect samples of different biologic media and then assesses their suitability for informing specific questions of health outcomes. For example, military per- sonnel who served in theater could be stratified by their exposures, focusing on those with the lowest and highest potential exposure to particular airborne hazards in order to maximize the signal to noise ratio. Biomarkers known to be associated with respiratory disease or biomarkers previously identified in other studies using the bioreposi- tory could then be examined. Another potential use of the biorepository would start with deployed personnel and then identify for analy- sis subgroups of service members who present with possible deployment-related illnesses. The availability and long-term stability of serum collected in the DoDSR makes it feasible to identify personnel with specific diseases decades after deployment and to compare their immediate post-deployment sera with sera from personnel with similar deployment who did not get ill. Each deployment may leave a distinct biologic signature that would permit exposure and internal dose assessments and biomarker analysis and thereby allow potential linkage with specific health effects. Taking Advantage of DoD/VA Health Record Integration Efforts  DoD and VA have been working toward a modernized and interoperable electronic health record (EHR) since at least 2013 (DoD, 2013). Those efforts are planned to first bear fruit in 2020 when such a system will be rolled out at so-called initial operating capabil- ity sites (VA, 2020), with complete interoperability between VA’s and DoD’s EHRs being phased in thereafter. An integrated system such as this—in addition to its primary goal of facilitating a secure and seamless trans- fer of the medical records of active-duty service members as they transition to veteran status—has the potential to enable investigators, with proper human subjects assurances, to far more easily access these data for research purposes. An integrated EHR system would also simplify the monitoring of respiratory health status (including lung function) over time, which is needed for investigations of outcomes that have long latency periods. In order to accomplish these objectives, the committee recommends that VA and DoD explicitly inte- grate research access considerations into their planning as they refine the implementation of their new i ­ nteroperable electronic health record system. It further suggests that, as part of this effort, VA and DoD commit resources to developing a database of research study data derived from the integrated records. Data integration is still at a relatively early stage, and it is important for VA to be planning now for how it might use the information derived from EHRs so that it can properly configure the system for access. There is also a plan to link EHRs with the individual longitudinal exposure records (ILERs) currently being developed jointly by DoD and VA. ILER combines (declassified) location, exposure, and health care–related databases (including DOEHRS-IH and the Defense Manpower Data Center) to create a complete record of a ser- vice member’s occupational and environmental health exposures over the course of his or her career by linking individuals to known exposure events and incidents and compiling the exposure history to distill and report the

ADVANCING THE UNDERSTANDING OF RESPIRATORY HEALTH ISSUES 209 relevant data and information. This application is in the final stages of development, and when it achieves full operational capacity in 2023 it will, among other capabilities, “[allow] near real-time creation of retrospective exposure registries sorted by location, exposure agent, or other demographic variables [and provide] a framework for identifying previously unknown health effects associated with environmental exposures” (DoD, 2019a). It thus has the potential to fill knowledge gaps by improving exposure assessment. The committee anticipates that the next few years will see the first studies using ILER data to characterize exposures of theater-deployed veterans. These initial efforts are likely to uncover strengths and weaknesses in the application of it as a tool in epidemiologic studies that should be identified and disseminated throughout the research community. Research Addressing the Mechanisms of Effects of Airborne Exposures Knowledge is lacking on how measured levels of environmental contaminants in serum, tissue, and the like translate to biologic effects and, separately, health outcomes. Among the areas of research of greatest relevance to studies of the health of theater veterans are basic science studies addressing biologic mechanisms and also those examining the biomarkers of effect and susceptibility. The potential for such research is illustrated, for example, by a study by Thakar et al. (2019), who developed an integrative network analysis linking clinical outcomes with environmental exposures and molecular variations in service personnel deployed to the Balad and Bagram bases in Iraq and Afghanistan, respectively, using samples from the DoDSR. Comparisons between personnel exhibiting new cardiopulmonary diagnoses after deployment start date and personnel exhibiting no symptoms identified biomarkers associated with cardiopulmonary conditions. It provided a proof of principle establishing a computational framework for an integrative analysis of deployment- related exposures, molecular responses, and health outcomes. Biologic Mechanisms Research Much of the research to date regarding the biologic mechanisms that may underlie health effects related to airborne exposures has focused on PM2.5. Some recent publications illuminate the state of the literature. A 2018 review article by Cho et al. identifies the potential mechanisms, stating that the components of PM2.5 responsible for cellular toxicity—including free radicals, organic chemicals, and transition metals15 on particle surfaces—may induce or produce reactive oxygen species that impair cellular-level physiologic and biochemical processes by inducing oxidative stress, inflammation, genotoxicity, and other effects that alter the normal physiological func- tions or fates of target cells, thereby resulting in tissue and organ damage. Several investigators have used in vitro experimental studies to examine PM2.5-induced cell damage and have discovered a variety of ways in which exposure affects methylation, signaling, and cell viability. Wei and Tang (2018) examined how airborne PM2.5 exposure affects the pulmonary immune system. They focused on the regulation of immune responses, observ- ing that while a number of studies indicate that PM2.5 exposure may modulate the Th1/Th2 balance16 by altering the expression of transcription factors, the details of this mechanism had yet to be elucidated. Platel et al. (2020) looked at genotoxic effects. The researchers—who used in vitro comet, micronucleus, and gene mutation assays of immortalized lung cell lines and primary normal human bronchial epithelial cells—found that PM2.5 and quasi ultra-fine (PM0.18) particles induced primary DNA damage but no chromosome aberrations in the immortalized cells. Furthermore, they did not observe in vitro genotoxic effects in primary normal human bronchial epithelial cells. Given these results and what is known about the relationship between PM exposure and lung cancer, the authors suggested that mechanisms other than genotoxicity, such as epigenetic alteration, deserved more research attention. 15  Transition metals are metals including vanadium, chromium, iron, nickel, copper, and platinum that are characterized in part by the ten- dency to easily form oxides. Sørensen et al. (2005) note that “soluble transition metals are abundant in the water-soluble PM fraction” (p. 1340). 16  T-helper (Th) lymphocytes play a role in immune function. Cells expressing the Th1 and Th2 profiles release different cytokines upon activation that influence host defenses against infection, modulate airway function, and orchestrate various cellular immune responses. The balance between the two profiles affects how the body responds to environmental insults (IOM, 2000a).

210 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES Separately, other investigators are exploring the use of animal models to better capture the complexity entailed in biological responses to airborne exposures. Curbani et al. (2019) conducted a review of this literature through the end of 2017. They found that the majority of PM studies had used mice or rat models. While inhalation better mimics the circumstances in which exposure occurs, it is technically difficult to standardize exposure levels, and intra-tracheal or nasal instillation was typically used in its place. The authors found that existing studies were characterized by a diversity of experimental protocols, which made it difficult to compare them. Importantly, the authors noted that the median PM inhalation rate from the experiments was three orders of magnitude higher than the rate found under ambient environmental conditions. These observations led them to conclude that the applica- bility of the results to human exposures and outcomes was open to question. Curbani et al. (2019) concluded that future animal studies need to address how to more accurately represent the conditions under which airborne expo- sure take place and to standardize how such exposures are managed in experiments to allow better comparability. These publications, along with those summarized earlier in the report, illustrate that airborne exposures and biologic mechanisms research has produced some provocative results but that it is still very much in its infancy, and there are a number of knowledge gaps that remain to be filled before the work can contribute materially to the understanding of human health effects. Research in areas outside of PM is lacking, as are studies that explore how to relate the results of cellular and animal models to humans. The committee thus believes that it would be desirable and feasible to expand the knowledge base by con- ducting further toxicologic studies using exposure parameters that realistically reflect the experience of those who have served in the Southwest Asia theater. Such studies should focus on inhalation studies of the primary airborne exposures of concern—burn pit emissions and PM from indigenous sources such as ambient dust and sand—and should mirror the composition, size, and concentration of these identified by exposure characterization research. The research should evaluate both short-term (days) and long-term (months) effects and include single, repeated, and intermittent exposures and appropriate negative and positive controls. Such studies are already being carried out by investigators and can and should be expanded. The committee observes that access is extremely limited to representative and well-characterized PM and dust from the Southwest Asia theater and comparison samples from non-theater military sites. The creation of standardized, representative samples of these materials for animal experiments would be a boon to researchers. The animal models used in these studies also need to reflect the realities of service in theater. This means moving from models that use only healthy young adults to models that allow for a better understanding of the effects of airborne exposures on those who are, for example, asthmatic or allergic, have other respiratory diseases or cardiovascular disease, or are obese. Studies that additionally factor in the effects of smoking or stressors like heat, blast, and noise would be particularly valuable. The committee also believes that studies of some other exposures that are not unique to the Southwest Asia theater but that are particular to the circumstances of military service are appropriate. These would include investigations of the effects of diesel exhaust, where there may be extended exposure to emissions from multiple vehicles in convoys; JP-8, a fuel used extensively by U.S. military aircraft and as an accelerant in burn pits; and CARC (chemical agent resistant coating), a paint that is applied to military vehicles to resist corrosion and chemi- cal warfare agents. In vitro toxicologic studies, while useful in the understanding of the basic biologic effects of particular chemicals and in elucidating mechanisms, are less likely to generate information relevant to veterans. Biomarkers of Effect and Susceptibility Research Human biomonitoring, in combination with environmental sample analysis, permits a greater understanding of the external sources of exposure and its relationship to internal dose, and it yields valuable information on the exposure sources and pathways. Advancing research on the biomarkers of effect and susceptibility, especially as it relates to the early identification of adverse outcomes—including those with known long-latency periods—is especially important in this regard. Such research could include studies of inflammatory, histologic, genomic, and metabolomic changes. Because unknown and transient exposures can cause long-term harm and often cannot be measured in real time, one way to assess exposure response is to use biomonitoring for chemical exposures and complement this

ADVANCING THE UNDERSTANDING OF RESPIRATORY HEALTH ISSUES 211 with measurement of biomarkers for biological responses (e.g., metabolic response patterns, cytokines, miRNA, and DNA methylation). High-resolution metabolomics for exposome research provides the capability to link exposures to internal dose to molecular responses to biomarkers of risk and health outcomes (Walker et al., 2016) using chromatography, high-resolution mass spectrometry, and chemometrics working together to provide a frame- work for high-resolution metabolomics. Gas or high-performance liquid chromatography separates the chemicals; high-resolution mass spectrometry measures the mass; and chemometrics allow for computation, data extraction, alignment, and characterization. Research Addressing Retrospective Exposure Characterization It is difficult to relate exposures to health outcomes without measurements of individual exposure, whether these come from biomarkers or a better understanding of the levels of contaminants in the environment. Research on these fronts is described below. Biomarkers of Exposure Research The complex composition of Southwest Asia theater airborne contaminants means that there are few data in the medical literature to help understand the half-lives of those contaminants in humans. However, trace ele- ments absorbed and retained in the biopsied lung tissues or other biospecimens (serum and urine, for example) of veterans may yield biomarkers of cumulative exposure to contaminants even after more than a decade of deploy- ment, depending on how these contaminants have been metabolized and eliminated. More accurate estimates of exposure to Southwest Asia theater airborne contaminants, as might be gained from trace element biomarkers, would almost certainly improve the accuracy of etiologic studies of disease suspected of being due to exposures. Examples of these analyses include 8-hydroxy-2'-deoxyguanosine and other oxidative stress biomarkers in human urine; melatonin in serum; thyroid hormones (including thyroxine [T]1, T2, T3, and T4) in the thyroid gland, brain, and serum; and iodine in serum. The feasibility of this approach was demonstrated in an animal inhalation study (Cohen et al., 2015) that showed that trace element profiles bearing the World Trade Center dust signature were retained in rat lungs 1 year post-exposure, mirroring findings in humans (Marmor et al., 2009). Research on biomarkers to assess environmental exposures and health outcomes in military personnel deployed to the theater is being pursued under the umbrella of the Military Biomarkers Research Study. This is a multiphase study sponsored by DoD that is intended to “assess whether biomarkers can be used to retrospectively assess deployment exposures and health impacts related to deployment environmental exposures” (Mallon et al., 2019). Phase I of the study examined the feasibility of using service members’ stored sera to assess biomarkers of internal dose and of effect, Phase II used available field measurements to evaluate whether there were correla- tions between these exposure surrogates and identified biomarkers, Phase III examined the relationships between these biomarkers and health outcomes, and Phase IV will investigate in vitro biomarker changes associated with exposures to chemicals of interest (Mallon et al., 2016, 2019). In brief, studies that were a part of the Military Biomarkers Research Study efforts have identified several novel miRNA biomarkers and metabolomic biomarkers, and significant associations were noted between deployment exposures, these biomarkers, and deployment health outcomes (Go et al., 2019; M. R. Smith et al., 2019a,b,c; Thakar et al., 2019; Thatcher et al., 2019; Woeller et al., 2019). Some of these are summarized elsewhere in this report, and all point to the potential for such research to better characterize in-theater exposures. To be successful, though, this research will need high-quality biospeci- mens that are acquired, handled, and processed in a standardized fashion that preserves their molecular integrity. Other Potential Exposure Characterization Research Research published in late 2019 found that “MOS (military occupational specialty) codes that were scored using a respiratory hazard exposure matrix may be helpful in characterizing some but not all inhalation hazards confronting land-based post-9/11 military deployers to Southwest Asia” (Zell-Baran et al., 2019, p. 1039). While such an approach has limitations—immediate needs in a deployed environment often lead service members to

212 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES perform tasks outside of their defined responsibilities—it has the potential to allow a more informed analysis of health outcomes in high-exposure-potential versus low-exposure-potential persons. This could be especially true for service members with multiple deployments or extended deployment to remote forward operating bases (which may entail additional or higher exposures to airborne contaminants due to the lack of an infrastructure for managing waste). The committee suggests that a feasibility study for constructing a specific job-exposure matrix for airborne hazards be considered as an exposure assessment tool. Zell-Baran et al. (2019) proposed that such work include “direct measurement of airborne particulate concentrations for higher hazard MOS codes and combat-related job duties” (p. 1039), which would serve to enrich and validate the model. Such a job-exposure matrix may also prove informative in interpreting the results of biomarker and other biomonitoring testing because certain occupational series or specialties may have differing -omic characteristics related to training- and occupation-specific exposures in addition to deployments. Remote Measurement and Estimation of Airborne Pollutant Levels Recent advances in technology present the opportunity to use satellite-based remote sensing observations to improve retrospective air quality assessments (EPA, 2019). There are several instruments aboard polar-orbiting National Aeronautics and Space Administration (NASA) and European Space Agency (ESA) satellites that retrieve atmospheric properties that can be related to air quality. Two such instruments that observe aerosol properties are the Moderate Resolution Imaging Spectroradiometer (MODIS) and the Multi-angle Imaging SpectroRadiometer (MISR). The Earth Observing System satellite Terra—which has both MODIS and MISR on board—was launched in late 1999 while Aqua—which has MODIS only—was launched in mid-2002 (ESA, 2020a,c). Both were still operating in early 2020. Recent algorithmic implementations of data from these instruments have resulted in aerosol optical depth17 retrievals at fine spatial (1 × 1 km for MODIS and 4.4 × 4.4 km for MISR) and temporal (daily for MODIS and weekly for MISR) levels that can be used in exposure assessments of PM for health effects studies (Garay et al., 2017; Lyapustin et al., 2018). Because the satellite sensors do not provide a direct measure of PM, it is necessary to calibrate the data against ground-level measurements in order to generate retrospective expo- sures, but some of the data needed to perform this exist. Ground measurements made through the DoD Enhance Surveillance Project at 15 sites in 2006–2007 (Engelbrecht et al., 2009) and at Joint Base Balad (CHPPM, 2008), for example, could be used for this calibration. The MISR instrument has the additional capability of distinguish- ing aerosol optical depth types (size, shape, absorption), which can be used to assess chemically speciated PM concentrations and thus source-specific profiles (Chau et al., 2020; Franklin et al., 2017, 2018; Meng et al., 2018). The Ozone Mapping Instrument aboard NASA’s Aura satellite also observes aerosols but since its launch in late 2004 has been primarily used for assessing the gaseous criteria pollutants ozone, nitrogen dioxide (NO2), and sulfur dioxide (Krotkov et al., 2016). At 13 km × 25 km, the Ozone Mapping Instrument has a relatively coarse spatial resolution for exposure assessment but is globally observing on a daily overpass schedule. It has been used to assess ground-level NO2 for the United States (Di et al., 2020) and over the Middle East (Daneshvar et al., 2017). TROPOMI (TROPOspheric Monitoring Instrument), a newer satellite (launched in 2017 by a consortium of European aerospace organizations), measures NO2 at better resolution than the U.S. instruments, and its data are also available to researchers through the ESA Copernicus Open Access Hub (ESA, 2020b; KNMI, 2020). For future exposure assessments, the most promising data source may be the upcoming NASA Multi-Angle Imager for Aerosols (MAIA) (Diner et al., 2018; Liu and Diner, 2017). The primary objective of MAIA, which is to be launched in 2022, is to assess the impacts of different PM2.5 (fine) and PM10–2.5 (coarse) species (sulfates, nitrates, carbons, dust) on human health. It builds on the MISR legacy to provide an integrated satellite-surface data collection and modeling strategy at fine (1 km × 1 km) spatial resolution that is tailored for assessing health effects. The challenge is that MAIA is a targeted mission, meaning that while it is polar orbiting it does not see the entire globe but rather targets particular areas for more detailed assessment. A target area covering an approxi- 17  Aerosol optical depth is a measure of light extinction through the column of the atmosphere and is a quantitative estimate of the abundance of aerosols in the atmosphere.

ADVANCING THE UNDERSTANDING OF RESPIRATORY HEALTH ISSUES 213 mately 300 km × 300 km region around Kuwait has been planned, though, and it is possible to implement others (M. Franklin, University of Southern California, personal communication, 2020). Remote Detection of Burn Pits Another emerging technology entails the repurposing of remote sensing observations of fires from the NASA Fire Information for Resource Management System database18 to identify historical burn pit activity. Through this system, global historical fire detections are available from the MODIS active fire product (Giglio et al., 2016). Fires are detected as thermal anomalies and represent the center of a 1 km pixel that is flagged by the Fire and Thermal Anomalies algorithm as containing one or more active fires from sources including biomass burning (Freeborn et al., 2014). Coupled with the locations of military bases and camps, MODIS active fire detections could assist in pinpointing the locations and assessing the durations of historical burn pits on or near in-theater operations. New Epidemiologic Studies of Respiratory Health Outcomes The committee is concerned that without changing the paradigm for how epidemiologic studies of respiratory health outcomes are conducted, many questions regarding their possible association with Southwest Asia theater expo- sures will remain unanswered. To address this it has developed some alternative study designs that it believes would lead to more definitive results. For the reasons presented below, the committee does not offer these as research recom- mendations but rather as illustrations of the kind of prospective information gathering that is needed to perform infor- mative respiratory health assessments of military populations that are subject to environmental exposure hazards. Two designs for studies of COPD are presented as examples; these could be adapted for other respiratory health outcomes. The study designs highlight the need for improved characterization of pre- and post-deployment lung function in combination with better measures of actual exposures in theater. Because—in the specific case of COPD—both the level of and the change in pulmonary function are required to assess the degree of presence and severity of obstructive (as well as restrictive) pulmonary disease, the study designs require pulmonary function testing to be done in a standardized manner so as to allow a comparison of the outcomes over time. In addition, repeated measures in well-characterized populations are called for to measure short-term reversibility. Illustrative Study Design 1 The first illustrative study design developed by the committee uses what might be termed a “prospective wave” approach. It would best be accomplished via a joint effort between DoD and VA to establish a cohort of personnel selected with the characteristics indicated below. The cohort would be followed for a minimum of 15 years with examinations every 3 years. It would be made up of three age groups—18–24, 25–34, and 35–44 years of age—of approximately 5,000 subjects each that constitute a representative racial/ethnic sample. To the degree possible, the persons would be active-duty personnel at the beginning of the study. A prospective wave design offers the opportunity, if the sample is appropriately selected, to provide an assessment of risk over an extended period of time, extending from age 18 to age 60, and to allow varying degrees of latency to be assessed. Because it will be important to be able to track and assess these subjects repeatedly over time, appropriate incentives and a commitment at the time of enrollment would need to be considered. To the degree possible, detailed exposure data gathered from the time of enrollment onward would be part of the study. These data might combine historical records with the best available current and developing technology. Upon enrollment, subjects would complete standardized questionnaires, pulmonary function assessments carried out by uniformly trained technicians, and a thorough health examination performed by a medical professional. The assessments would be repeated every 3 years, and an effort would be made to capture all major medical events that occurred between examinations. Because there is significant effort that must be committed to establishing such a cohort and the cohort would obviously be well characterized, it clearly could be used in a “nested case–control” fashion to answer a 18  See https://firms.modaps.eosdis.nasa.gov (accessed July 1, 2020).

214 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES number of questions outside the domain of chronic respiratory disease. In addition, as the field of “omics” becomes more sophisticated, it would be important to obtain biologic specimens on these subjects. Illustrative Study Design 2 The second illustrative study design developed by the committee is less ambitious than the first alternative but could be accomplished more quickly and easily and with fewer resources. This study would more generally examine pre-deployment versus post-deployment health status. It would test the premise that in-theater exposures could cause new-onset COPD over a relatively short period of time, similar to what was observed in post-9/11 New York City rescue workers (firefighters and EMS personnel) (Aldrich et al., 2010)—a scenario that is arguably more relevant to the 1990–1991 Gulf War exposure setting. It is in contrast to the approach taken by many of the COPD studies examined by the committee that were based, at least implicitly, on what is known about the relationship between cigarette smoking and COPD, where the disease develops over a long time period and is associated with an extended history of exposure. In the study design presented here, pre-deployment spirometry would be used to identify a cohort of previously nondeployed participants without pre-existing COPD, using the Global Initiative for Chronic Obstructive Lung Disease (GOLD, 2018) or other appropriate criteria. Both pre- and post-bronchodilator spirometry data would be desirable in order to exclude participants with pre-existing asthma. Pre-deployment participant data would ideally include demographic information, respiratory illness history, smoking history, and family history of respiratory disease. In light of the anticipated low likelihood of developing new-onset COPD, a relatively large cohort would be needed. Table 5-1 shows the required sample size for different detectable exposure effect sizes, assuming that a multiple logistic regression model and a dichotomized exposure were used in the analyses. The five scenarios demonstrate the effect of different assumptions on sample size. Rigorous exposure estimation would be essential to such an analysis. This might be accomplished using a com- bination of point predictions of concurrent spatio-temporal ambient air pollution concentrations, the documentation of participants’ locations in theater, and contemporaneous ground measurements to validate modeled estimates if available. Covariate data would ideally include cigarette smoking, combat experience, and blast exposure. Vari- able timeframes for post-deployment pre- and post-bronchodilator spirometry could be factored in, ranging from immediately after deployment to later times after return from deployment, although testing immediately after deployment and 1 year later would likely be adequate in light of the presumed natural history of COPD in this setting. It would be desirable if post-deployment spirometry was performed using the same protocol as the pre- deployment exam, with spirometry technicians blinded to exposure. The primary analysis would use multiple logistic regression models to evaluate the risk of developing COPD (assessed using post-deployment spirometry data), related to the degree of exposure, while controlling for effects of smoking and other covariates. Aldrich et al. (2010) found that forced vital capacity (FVC) declined to a lesser extent in concert with the fall in forced expiratory volume in 1 second (FEV1) in the 9/11 firefighters, suggesting that FEV1/FVC may not be able to reliably detect COPD onset. Therefore, in a secondary analysis, a 5% decline in percent predicted FEV1 (to account for potential lung growth between the pre- and post-deployment exams), or approximately 200 mL from the pre-deployment level without a significant improvement after bronchodilator, could be used to define new-onset COPD. This secondary criterion is presumed to be more sensitive than FEV1/FVC in detecting new-onset COPD with consequent smaller sample size requirements (see Table 5-1 Scenario 5). This proposed study design would include the following advantages: • a comparison group composed of concurrently deployed personnel; • an objective measure of outcome; • a relatively short study duration; • individual-level estimates of airborne exposures, ensuring a wide range of exposures; • adequate power to detect an association with exposure; • control for cigarette smoking; • a means of accounting for potential lung growth in this relatively young cohort; and • exclusion of participants with asthma either before or after deployment.

ADVANCING THE UNDERSTANDING OF RESPIRATORY HEALTH ISSUES 215 TABLE 5-1  Required Sample Sizes to Detect COPD in a Hypothetical Pre- Versus Post-Deployment Study of Theater Veterans, as a Function of Various Assumptionsa Scenario Covariate: COPD OR Prevalence of COPD Exposure OR Required Sample Size 1 1.2 0.05 1.10 77,525 2 1.1 0.05 1.10 79,532 3 1.2 0.05 1.05 304,318 4 1.2 0.02 1.10 191,564 5 1.2 0.10 1.10 42,405 NOTES: Changes from the Scenario 1 assumptions are bolded. Common assumptions: covariate-exposure OR = 1.1; 2-sided p-value = 0.05; power = 0.80. COPD, chronic obstructive pulmonary disorder; OR, odds ratio. a Sample sizes calculated using “Power/Sample Size Calculation for Logistic Regression with Binary Covariate(s).” See https://www.­ dartmouth.edu/~eugened/power-samplesize.php (accessed June 15, 2020). Its disadvantages include the large number of participants needed, the fact that it would not pick up delayed development of COPD over the longer term, and the potential that some participants developing deployment-related asthma could still potentially be mistakenly included. Observations Regarding the Illustrative Study Designs The two designs developed by the committee would address many of the flaws identified in the epidemiologic studies reviewed in this report. However, there are reasons why such approaches have not been implemented by the research teams who have been and are trying to understand whether in-theater airborne exposures are result- ing in adverse respiratory health outcomes in the Southwest Asia theater veterans. Primary among these is that pre-deployment lung function data were generally not collected, and there are far too few service members being deployed now to mount an informative study. The committee, as discussed in Chapter 4, does not believe that the issue of the utility of gathering pre-deployment lung function data for the purpose of surveillance has been resolved. Such data collection would be costly and time consuming but would greatly aid the evaluation of respiratory health outcomes in the future. This program could begin with a cohort of military occupational specialties that are more likely associated with deployment exposures, prior to expanding to other service members. The U.S. Congress and federal government will need to evaluate whether the upfront costs of performing this and other health status benchmarking yield sufficient benefits in the long term when service members become veterans and questions arise regarding whether a particular health problem may be associated with military service. Other Research Opportunities Studies of Non-Military Personnel Providing In-Theater Support Services DoD civilian employees and contractors play a large role in delivering in-theater services to the U.S. military, including activities such as waste management, base security, and transportation, that may have entailed significant exposure to airborne hazards (DoD, 2019b; Schwartz and Church, 2013). Specific concerns have been raised about the health of DoD contractors who were exposed to burn pit emissions (Chiaramonte, 2016). However, data on the health of these personnel are not systematically collected, and the committee identified only one analysis of respiratory health outcomes in the population (Krefft et al., 2017). Non-military personnel serving in theater thus represent an untapped source of information on airborne exposures and the respiratory health outcomes resulting from them. DoD delivered health care to private-sector personnel while they were deployed and billed the cost to their employers (DoD OIG, 2012) so documenta- tion must exist. The committee acknowledges that there would be considerable barriers to accessing such ­nformation—not just those involved with the protection of personally identifiable information but, more fun- i

216 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES damentally, the potential reluctance of contractors to allowing access to data on their employees. Nonetheless, contractors have been an important component of U.S. deployments to the theater. Studying health outcomes in this population would provide information that would benefit service members, veterans, and the civilian employees themselves. NEWLY EMERGING TECHNOLOGIES TO ADDRESS KNOWLEDGE GAPS Previous sections of this chapter have already identified many of the major technologies that will help to better characterize airborne exposures in Southwest Asia theater veterans. These include satellite measurements of PM, other pollutants, and burn pits—combined with advances in data processing—to estimate past ambient levels, biomarker discovery (including the algorithms that allow for the rapid screening of candidates), and the rapidly evolving field of -omics (epigenomics, genomics, metabolomics, proteomics, etc.) that help to bring about a comprehensive understanding of how airborne exposure affects humans. While VA’s responsibility lies with persons who have completed their military service, the committee thought it appropriate in this section to briefly touch on some of the new technologies that might be brought to bear to gather information during active duty that would aid in the future evaluation of airborne exposures and health outcomes. Four examples are offered below. The challenge is that any technology, no matter how effective or well intentioned it is, will take a back seat to the exigencies of operating in the field. It will not gain acceptance unless it can be seamlessly incor- porated into operations, can be used in a way that does not encumber or otherwise limit personnel, and does not compromise their security. That said, there appear to be multiple technologies that hold the promise of developing information on active duty personnel that would later aid VA in its evaluation of the health effects of military exposure to airborne agents. While it will be the responsibility of DoD to develop and deploy such technologies and to gather and maintain the information they generate, VA has a role to play in defining the type and form of that information that would be most useful, in fostering studies that take advantage of the information to better understand health outcomes in veterans, and in keeping abreast of advancements in health and benefits domains that they do have responsibility for that might feed into the development of exposure assessment technologies. Silicone Wristbands for Exposure Detection Silicone wristbands have been developed for use as personal passive samplers capable of sequestering organic compounds as measures of an individual’s external exposure. Research indicates that they are capable of capturing and detecting more than 1,500 chemicals (Dixon et al., 2019). Silicone wristbands have been identi- fied as a possible means of exposure assessment in military settings (Horne et al., 2020), and some small-scale testing has been performed with them (Hardos et al., 2019). An October 2019 presentation to the committee by Jennifer Therkorn of the Johns Hopkins University Applied Physics Laboratory reported the results of a proof-of-concept field test of silicone wristbands’ potential to detect fuel vapors which was conducted for the Army Public Health Center. The test concluded that the wristbands provided reliable, simple, cost-effective, yes/no profiling for organic compound detection. The investigators noted, though, that they could not provide information on concentrations and that the correlation between detection of and actual exposure to airborne agents was unknown (Therkorn, 2019). The committee understands that further research is being conducted by DoD on the utility of wristbands as an exposure assessment tool. Advances in Exposure Monitoring Applications for Deployed Environments A 2019 request for information (RFI) issued by DoD’s Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense in collaboration with the Defense Health Agency (DHA) identi- fied several potential near-term (2019–2024 timeframe) innovations in exposure monitoring applications for deployed environments (JPEO-CBRND, 2019). The intent was to solicit ideas for low-cost technologies that

ADVANCING THE UNDERSTANDING OF RESPIRATORY HEALTH ISSUES 217 could be used to support real-time health risk assessment and mitigation decision making and generate data that could be made a part of individual longitudinal exposure records. The RFI classified these prospective technologies into a number of categories: • “outward looking” wearable environmental hazard detectors or samplers; • “inward looking” wearable physiologic status, health effects, and biomarker monitoring applications (non- invasive and invasive in vitro and in vivo devices and validated model of health effects) with sensing applications integrated with existing DoD on-body communications devices; • point or handheld sensors for toxic industrial chemicals and toxic industrial materials; • miniaturized, unattended ground sensors for area hazard monitoring or meteorological data collection; • lightweight power solutions for sensor applications; • geotagging and timing devices (for individuals and also those able to be added to existing point and areas sensors); • portable field analytical platforms for rapid, on-site analysis of collected environmental samples for toxic industrial chemicals and materials; and • self-sampling devices for the collection and preservation of clinical sample matrices while deployed, related to post-deployment lab analysis of transient biomarkers of exposure or effect (JPEO-CBRND, 2019). The RFI also sought information on validated biomarkers for pre-disposition and pre- and post-deployment screening for exposure or for the health effects of ambient environment and manmade environmental hazards. The committee understands that, as of early 2020, elements of this RFI have been initiated. If such technologies were to be developed and implemented in the future, they would not only inform retro- spective exposure assessments but would also generate information that field commanders and medical support personnel could use to lower exposure potential by, for example, limiting outdoor missions or elective activities or providing personal protective equipment on “high exposure” days. Low-cost sensor technology to measure levels of airborne agents at fixed locations such as bases—which could in turn be coupled with remote sensing data—could be used in the same manner. Such devices would need to be hardened to function reliably in the extreme environments in which military operations often occur, small and light enough to not further encumber personnel, and able to transmit their information in a manner that did not compromise the security of forces. Wearable and Portable Devices to Assess Intermediate Health Outcomes Wearable devices are increasingly common in real-world settings and are being applied in research stud- ies. Smart watches monitor rest/activity cycles, heart rate, and sleep patterns. Handheld spirometry includes electronic data capture for serial use as a personal device. Systems that are larger than personal samplers but more amenable to field-based research are increasingly available to assess respiratory physiology beyond spirometry. Measurements of gas transfer (diffusing capacity of carbon monoxide) and airway mechanics (impulse oscillometry) can be made with lower-cost, portable equipment and may provide additional insight concerning the effects of environmental exposures on respiratory health. Exhaled gases, such as nitric oxide, can be measured with portable devices as a non-invasive assessment of airway inflammation. Technology to assess sleep-disordered breathing has moved from lab-based to home-based testing in clinical practice. In research, sleep studies are performed remotely with equipment that can be shipped and self-applied. These innovations have increased the scale of research that can be conducted to address gaps in understanding of the prevalence and risk factors for sleep-disordered breathing among military personnel and veterans at home and, eventually, in deployed settings. Advances in Epigenetic Monitoring The Defense Advanced Research Projects Agency (DARPA) is fostering research aimed at developing a field-deployable epigenome “reader” for the real-time evaluation of exposure threats. The goal of the ­ pigenetic E

218 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES C ­ haracterization and Observation program is to “identify and discriminate epigenetic signatures created by expo- sure to threat agents and to create technology that performs highly specific forensic and diagnostic analyses to reveal the exact type and time of exposure” (DARPA, 2018). While focused on the detection of weapons, the technology could have application in identifying exposures to airborne agents. ORGANIZATIONS THAT VA MIGHT PARTNER WITH TO ADDRESS KNOWLEDGE GAPS A number of federal agencies, investigators in the United States and abroad, and other governmental and private-sector organizations are currently conducting research relevant to theater veterans’ health or else have information that could improve the conduct of such work. These entities are listed in the sections below. While the committee offers one specific recommendation regarding partnering, it identifies a broad range of organizations that have potentially useful exposure or health information that VA should consider collaborating with in order to address specific needs and pursue new research opportunities. Department of Defense VA already partners extensively with DoD on issues related to the effect of occupational and environmental exposures on military and veteran health. The organizations related most closely to the evaluation of respiratory health issues are noted below. Defense Health Agency DHA is a joint, integrated combat support agency tasked with providing “a medically ready force and ready medical force to Combatant Commands in both peacetime and wartime” (DoD, 2020a). As part of this task, DHA (within the Occupational and Environmental Health Branch of its Public Health Division) is responsible for DOEHRS-IH, which captures military occupational and environmental health risk data and actively tracks biologic, chemical, physical, and other health hazards (DHA, 2018).19 These are consolidated into a web-based application that can be used for risk management and epidemiologic studies. DHA also leads the DoD component of a joint effort with VA, the ILER web-based application, discussed earlier in the chapter. The challenge will be to integrate such information with other sources, such as DoD site sampling (DOEHRS-IH) data and NASA satellite observations (discussed below), to paint a more complete picture of individual exposures and refine the periodic occupational and environmental monitoring summary. The Armed Forces Health Surveillance Branch also resides within DHA’s Public Health Division. It is respon- sible for the DoDSR (mentioned earlier in this chapter) and DMSS, a relational database containing personnel (including military occupational specialty codes), medical (in-patient, ambulatory, reportable event, immunization, and prescription information), laboratory (serologic specimens, chemistry and microbiology results), and deploy- ment (including pre- and post-deployment health assessments) data throughout service members’ careers (DHA, n.d.). DMSS data have proven utility in studies of respiratory health outcomes in theater veterans, having been used in studies of respiratory diseases (Rohrbeck et al., 2016), respiratory pathogens (Eick et al., 2011), sarcoidosis (Forbes et al., 2020), and biomarkers of exposure (Mallon et al., 2019; Thakar et al., 2019; Thatcher et al., 2019). Mallon et al. (2016) assert that the linking of DMSS data with other information resources “provides a powerful epidemiological resource that allowed us to investigate the relationship between deployment burn pit exposures, serum biomarkers, and potential health outcomes.” However, there is a major obstacle to fully exploiting DMSS information: the lack of an interoperable DoD–VA EHR and the subsequent difficulties in combining active-duty and post-service medical data held by the depart- ments. This is a long-standing and complex issue that DoD and VA have been working on for several years. The 19  DOEHRS-IH and ILER are also described in Chapter 3 in the section “Exposure Tracking by DoD.”

ADVANCING THE UNDERSTANDING OF RESPIRATORY HEALTH ISSUES 219 VA–DoD joint strategic plan for fiscal years 2019–2021 lists interoperability as a strategic goal, and the following is one of its objectives: Objective 4.1—Electronic Health Record Modernization Interoperability—Enhance health data interoperability between VA, DoD, and their private partners as VA and DoD continue their electronic health record (EHR) modern- ization efforts. (VA–DoD Joint Executive Committee, 2019, p. 5) VA indicates that its EHR modernization effort, which has interoperability with DoD as a primary component, will go live in spring 2020 and is scheduled for completion in 2026 (P. Hastings, Veterans Health Administration, personal communication, February 20, 2020; VA, 2020). The committee notes that while this effort does not have the facilitation of epidemiologic research as a primary objective, more seamless integration will greatly enhance such work. DoD and DoD-Affiliated Biorepositories DoD maintains or supports a number of biorepositories that store materials of potential utility to studies of respiratory health outcomes in theater veterans, Prominent among these, as already noted, is the DoDSR. Mancuso et al. (2015) noted that as of 2015 more than 80% of the repository’s specimens were linked to individual health outcomes data, the result of an effort that began in 1990. DoDSR-supplied specimens have been used in studies of biomarkers, including the Military Biomarkers Research Study (Go et al., 2019; Mallon et al., 2019; M. R. Smith et al., 2019a,b,c; Thatcher et al., 2019), and have great potential in future investigations in this area. Another major DoD biorepository is maintained by the Joint Pathology Center (JPC), which serves as the central repository for collected biologic materials submitted for consultation by military, other government, and civilian medical providers (IOM, 2012). JPC’s holdings include three relevant war-related registries—Kuwait/ Persian Gulf War, Operation Iraqi Freedom/Iraq Service, and Operation Enduring Freedom/Afghanistan Service— plus one registry focused on specimens of service members with embedded depleted uranium. There are many challenges associated with the research use of these specimens, but they are nonetheless a resource for pathology- related research. Ladich et al. (2002), for example, conducted a histopathologic study of head and neck specimens in the Kuwait/Persian Gulf War registry that found a number of cases of chronic sinusitis and allergic rhinitis but few neoplasms (which the authors speculated was a consequence of the relatively young age of the cohort). JPC pathologists additionally could serve as a source of expertise on difficult-to-interpret pathologic specimens and have done so in the past on cases of suspected constrictive bronchiolitis (Lewin-Smith et al., 2015; Madar et al., 2017). The 2018 National Academies publication Feasibility of Addressing Environmental Exposure Questions Using Department of Defense Biorepositories: Proceedings of a Workshop—in Brief highlighted additional ­biorepositories that hold materials that may be of use in studies of Southwest Asia theater veterans (NASEM, 2018a). One of these is at the John P. Murtha Cancer Center. The biorepository there is a joint effort of DoD, the Uniformed Ser- vices University of the Health Sciences, and the Walter Reed National Military Medical Center that collects and maintains biospecimens (including tissue, blood, urine, and saliva) from patients in military hospitals who have been diagnosed with, or are suspected to have, a malignancy. It has other information, including self-reported environmental exposures, related to some specimens. The other biorepository was assembled in support of the Army Study to Assess Risk and Resilience in Servicemembers and the Study to Assess Risk and Resilience in Servicemembers–Longitudinal Study. One component of this effort was a study of soldiers assigned to service in Afghanistan that obtained blood samples and survey data before the soldiers’ deployments and reassessed the subsets of the cohort 1, 3, and 9 months after they returned from deployment (Ursano et al., 2014). The complete collection includes whole blood and plasma, buffy coat, and DNA aliquots. The specimens and associated data in these biorepositories were not collected with the intent of studying the effects of in-theater environmental ­ exposures on respiratory health outcomes, but it is possible that they contain information that might be useful in such studies, especially if they were combined with data from other sources. The committee did not identify any such studies to date, but representatives of the repository have indicated that they would make their materials available to other investigators upon application (NASEM, 2018a).

220 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES While it is not under DoD’s aegis, the biorepository assembled as part of the Detection of Early Lung Cancer Among Military Personnel (DECAMP) series of studies receives support from DoD under its lung cancer research program, which is in turn a part of the Congressionally Directed Medical Research Programs (CDMRP).20 The DECAMP consortium includes military treatment facilities and VA hospitals. Biospecimens collected in the research effort include nasal brushings, serum, plasma, and intrathoracic airway samples (bronchial brushings and bronchial biopsies) from normal-appearing airway epithelium; computed tomography (CT) scans obtained during routine clinical care are also part of the database (Billatos et al., 2019; Spira and Moses, 2017). These are currently being used for studies of biomarkers and gene expression. It is not clear from published information whether and to what extent the subjects may include theater veterans. A 2019 paper on the cohort indicated that data sets were still being generated and that data sharing would not be available until after the completion of study enrollment (Billatos et al., 2019). The Boston Biorepository, Recruitment, and Integrative Network for Gulf War Illness is a CDMRP-funded biorepository network that also has potential to inform studies of theater veterans’ health outside those that are its focus. Kimberly Sullivan, the principal investigator, and Nancy Klimas gave a presentation to the committee on this network during its October 2019 workshop (Sullivan and Klimas, 2019). Their inventory includes whole blood, serum, plasma, buffy coat, urine, and DNA samples. DoD and Armed Forces Research Organizations DoD and the service branches maintain a number of other organizations that generate knowledge in support of DoD’s mission. Two of these that conduct or support research relevant to the evaluation of the effects of airborne exposures have already been cited in this chapter. AFRL is performing innovative biologic and toxicologic research on the effects of burn pit exposures using animal models (DelRaso et al., 2018; Mauzy, 2019), while DARPA is sponsoring cutting-edge work on a device that could identify the epigenetic “fingerprint” of adverse exposures in the field (DARPA, 2018). Both organizations are generating information that may inform future studies of theater veterans’ health, and VA could choose to help shape that work via collaboration to better address its needs. Concluding Remarks Concerning Partnerships with DoD VA thus already partners extensively with DoD and is well aware of the usefulness of this relationship. These collaborations are yielding benefits for both service members and veterans in the form of information that may be used to identify, manage, and cope with potentially harmful exposures. The committee recommends that VA continue and expand its partnership with DoD on environmental health issues, focusing on the free flow of information on exposures encountered during military service and the health of personnel before, during, and after deployment and after transition to veteran status. This should include cooperation on identifying which respiratory health status information should be gathered during active duty for later use as baseline data in evaluating veterans’ health for treatment, benefits, and research purposes. Researchers Conducting Studies of Theater Veterans’ Health There are a number of epidemiologic studies and research centers that address respiratory health issues in South- west Asia theater veterans. Some of these are under the guidance of VA investigators—the Airborne Hazards and Burn Pits Center of Excellence; the Comparative Health Assessment Interview, Million Veteran Program, National Health Study for a New Generation of U.S. Veterans, and Service and Health Among Deployed Veterans studies; and the Gulf War Era Cohort and Biorespository project—while others, such as the Millennium Cohort Study, Military Biomarkers Research Study, and Study of Active Duty Military for Pulmonary Disease Related to Environmental 20  See https://cdmrp.army.mil/lcrp/default (accessed August 11, 2020). The operation of the Congressional Directed Medical Research Pro- grams is addressed in the 2016 National Academies report Evaluation of the Congressionally Directed Medical Research Programs Review Process (NASEM, 2016a).

ADVANCING THE UNDERSTANDING OF RESPIRATORY HEALTH ISSUES 221 Deployment Exposures, are being conducted under DoD sponsorship and the aegis of DoD principal investigators. In addition to the guidance that VA provides to its own investigators on future research directions coming out of this report, the committee believes that there are partnering opportunities with these initiatives related to both new analyses of existing data and the collection of data to address knowledge gaps. The National Academies 2018 report Gulf War and Health: Volume 11 noted this potential. While it was referring to research on the generational health effects of theater exposures, its observations are also applicable to respiratory health effects: [T]he committee proposes … to leverage ongoing veterans’ health research programs, such as the Million Veteran Program and the Millennium Cohort Study. Such an approach would greatly benefit from past investments and take ad- vantage of existing infrastructure…. These programs … have already enrolled large cohorts and are linked to a variety of rich big data sources, and some of them already have in place protocols for the collection of biological specimens. This committee has made clear its concerns about the often selective nature of the study participants involved in these efforts and other weaknesses that limit the extent to which informative studies can be performed with these populations. Nevertheless, there are areas where fruitful additional research can be performed. Other U.S. Federal Agencies National Aeronautics and Space Administration As detailed earlier in this chapter, NASA and ESA administer satellites and airborne and ground-based obser- vation projects that collect environmental data that can be used to model ground-level exposure to airborne agents. Their instrumentation is capable of providing information on parameters associated with PM (aerosol index, aerosol optical depth), carbon monoxide, nitric acid, nitrous oxide, ozone, and sulfur dioxide as well as information on dust storms and fires (NASA, 2020). Data sets for some of these go back several years, allowing for retrospec- tive estimation of levels. Much of the research related to health issues is focused on PM and, in particular, PM2.5. This includes work sponsored by VA under its Cooperative Studies Program that has demonstrated how satellite data can be used to estimate historical PM2.5 levels in the theater (Chudnovsky et al., 2017; Masri et al., 2017a,b). Diao et al. (2019, p. 1391) highlight the challenges associated with such modeling: We find inconsistencies among several publicly available PM2.5 estimates, highlighting uncertainties in the exposure datasets that are often overlooked in health effects analyses. Major differences among PM2.5 estimates emerge from the choice of data (ground-based, satellite, and/or model), the spatiotemporal resolutions, and the algorithms used to fuse data sources. This suggests that further and more in-depth research in the area would be appropriate. A VA partnership with NASA could help to address these challenges in a way that generated information that would aid in characterizing theater veterans’ exposures. The discussions of new technologies and feasible research above highlight the potential of such of a partnership. National Oceanic and Atmospheric Administration The National Oceanic and Atmospheric Administration (NOAA), like NASA, has a robust research effort centered around the collection and analysis of atmospheric data—information that can be applied to models of exposure to airborne agents. NOAA’s Air Resources Laboratory is the home of a tool that has been used to help characterize airborne hazards levels and exposures: the Hybrid Single Particle Lagrangian Integrated Trajectory (HYSPLIT) is a transport and dispersion modeling system that can be used to retrospectively construct site exposure profiles (Stein et al., 2015; Wardall and Grabinski, 2018). It has been used by investigators in studies of veterans (Rinker, 2011; Smith et al., 2002) and, more generally, of Southwest Asia locations (Alolayan et al., 2013; Li et al., 2020; Querol et al., 2019; Yassin et al., 2018). HYSPLIT is freely available and is implemented online as part of NOAA’s Real-Time Environmental Applications and Display System suite of applications (NOAA, 2020).

222 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES National Institute of Environmental Health Sciences The committee responsible for the 2018 National Academies report Gulf War and Health: Volume 11 (NASEM, 2018b) cited work being conducted by NIEHS’s Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription program as an existing federal effort that might facilitate VA’s health research efforts. The program is focused on the development of epigenetic biomarkers in animal models for eventual application in humans (NIEHS, 2020). It is ongoing as of early 2020. The current phase has funded a consortium of universi- ties to pursue work characterizing epigenetic changes in tissues and cells induced by environmental exposures and to investigate the role of such factors as the timing of exposure. Wang et al. (2018) note that this includes investigating how blood, skin, and nasal epithelial cells might be used to investigate the effects of PM2.5 exposure on cardiopulmonary outcomes, a topic of direct relevance to studies of theater veterans. National Institute for Occupational Safety and Health The National Institute for Occupational Safety and Health (NIOSH) developed and maintains the Spirometry Longitudinal Data Analysis (SPIROLA) software tool, which helps researchers and medical professionals monitor and analyze variability in spirometry test results over time (Hnizdo and Halldin, 2015). The committee earlier con- cluded that there was insufficient evidence to draw a conclusion about the efficacy of pre- versus post-deployment spirometry in informing questions regarding the respiratory health of theater veterans or to offer advice about the circumstances under which such data gathering might be appropriate. Morris (2015, pp. 98–99) observed the following: An essential component for obtaining spirometry in a large group, such as a military population, would be a cen- tral database to collect, store, and track information aside from the current electronic medical record. Although many tracking systems exist for other military health issues, it would be burdensome to establish such a system for s ­ pirometry. Current electronic medical records in both DoD and VA do not allow the direct uploading of spirometry or other pulmonary test results into a predesignated section. Results are generally scanned in with PDF (Portable Document Format) files and located in different places in the medical record, severely limiting searching for results. SPIROLA provides electronic transfer of standardized data output from spirometers to health records in an occupational setting. Thus, if a decision was made to pursue the systematic collection of pre- and post-deployment spirometry information, then it would be important to establish such a capability, and it would benefit VA to partner with NIOSH to determine how best to use, adapt, or extend SPIROLA in a manner that would allow for easier transfer of its data to VA medical records for both screening and research purposes. Department of State The Department of State stations personnel around the globe in support of the nation’s foreign policy goals, including U.S. service members who are detailed to provide military liaison with foreign governments and security at some locations. The adverse effects of airborne exposures on staff and their families is of great concern to the department,21 which has partnered with the Environmental Protection Agency to establish and manage the AirNow Department of State program.22 AirNow has real-time and historic ozone and PM2.5 measurements for a number of locations, including Kabul, Afghanistan; Manama, Bahrain; Bagdad, Iraq; Kuwait City, Kuwait; and Abu Dhabi and Dubai, United Arab Emirates. While they are single-site observations, they provide a means for validating other measurements and proxies used in exposure characterization and epidemiologic studies. It may also be possible to 21  For example, the Department of State requested the National Academies to establish the Standing Committee on Medical and Epide- miological Aspects of Air Pollution on U.S. Government Employees and Their Families in 2016 to “provide a forum for discussion of scien- tific, technical, and social issues relevant to effective health management and protection of family members assigned to overseas locations with severe air pollution” (https://www.nationalacademies.org/our-work/standing-committee-on-medical-and-epidemiological-aspects-of-air- pollution-on-us-government-employees-and-their-families [accessed August 11, 2020]). 22  See https://www.airnow.gov/international/us-embassies-and-consulates (accessed August 11, 2020).

ADVANCING THE UNDERSTANDING OF RESPIRATORY HEALTH ISSUES 223 gain insights from marrying AirNow data with health information on the military personnel serving at these sites since their dates of deployment and locations would be better known than is the case for many others (although the relatively small numbers of persons involved might limit the usefulness of the analyses). Other Nations Involved in the Southwest Asia Theater of Military Operations A coalition of nations have taken part in military operations in the Southwest Asia theater since 1990. Studies of respiratory health issues have been performed on the personnel involved in these operations. Chapter 4 cites some of these, including investigations of veterans of the militaries of Australia (Davy et al., 2012; Ighani et al., 2019; Sim et al., 2003, 2015), Canada (Statistics Canada, 2005), France (Salamon et al., 2006), Poland (­ orzeniewski K and Brzozowski, 2011; Korzeniewski et al., 2013), Sweden (Saers et al., 2017), and the United Kingdom (Cherry et al., 2001; Unwin et al., 1999). In addition, Canada (Robinson, 1995) and the United Kingdom (Coker et al., 1999) have established health registries of veterans involved in the 1990–1991 conflict (Gray and Kang, 2006). The Australian Department of Veterans’ Affairs maintains the Preliminary Gulf War Nominal Roll, which lists Australian Defence Force personnel involved in that conflict (Australian Government DVA, 2019). Although studies of coalition partners have much smaller numbers of potential subjects than those of U.S. veterans, research is aided by the more detailed information on health status and outcomes available through these nations’ national health programs. It is also the case that these forces were deployed in more limited areas, which allows for easier estimation of potential exposures. As mentioned earlier—in contrast to many of the studies of theater veterans from the United States—several studies of European veterans have been able to achieve relatively good participation rates, which may provide insight into how future U.S. studies could be improved. For example, Cherry et al. (2001) realized a response rate of 85.7% of the 4,755 eligible UK service personnel deployed to the 1990–1991 Gulf War. Participation rates were higher in active-duty service personnel (93%) than in those who had left the service (80%). In the Danish Gulf War Study (Ishoy et al., 1999), of those deployed in the 1990–1997 period as part of the United Nations peacekeeping mission, 686 (84%) participated while 231 (58%) of the eligible randomly selected nondeployed service members took part. For the Australian Gulf War Veterans’ Health Study’s baseline cohort, 1,456 Gulf War veterans (81% of those eligible) and 1,588 comparison group members (57% of those eligible) participated (Ikin et al., 2017). These rates of participation are all better than is typical of U.S. studies. For example, in the M ­ illennium Cohort study (Smith et al., 2009), the initial response rate was 37%, of which 60% remained for follow-up (22% participation overall), and 85% of those were eventually included in the data analysis, yielding a 19% participation rate overall. There is an open question, though, regarding whether something would be gained in attempting to partner with researchers who study forces from other nations to carry out future work. While it might be possible to obtain good response rates and to collect rich health outcome data by exploiting national health system resources, there are also some issues. The most obvious of these is the relatively small number of service members from other nations deployed to the Southwest Asia theater, which limits future studies to essentially all but studies of the more common health outcomes unless a spike is observed in a relatively rare disease. When coupled with questions about generalizability of findings from studies involving other nations to the U.S. military and veteran population, there would seem to be limited potential for realizing advantage from pursuing such partnerships. Health Care Providers More than 50% of military personnel do not enter the VA health care system after they leave the military (NASEM, 2018b). They may be eligible for TRICARE or TRICARE for Life through DoD,23 obtain services from private-sector health maintenance organizations or clinicians through their employer, pay out of pocket for care, or 23  TRICARE is DoD’s integrated, single-payer health services provider that combines the health care resources of military treatment facilities with networks of civilian health care professionals, medical facilities, and suppliers, TRICARE for Life provides supplementary coverage for TRICARE beneficiaries who have Medicare Parts A and B.

224 RESPIRATORY HEALTH EFFECTS OF AIRBORNE HAZARDS EXPOSURES use federal (Medicare/Medicaid), state (Medi-Cal in California, for example), or local options. VA thus only has direct access to the medical records of a subset of veterans, a subset whose demographics are not representative of the veterans cohort as a whole (Meffert et al., 2019). This means that outside of the information developed in the epidemiologic studies cited in this report and those like them, relatively little is known about the health of many in-theater veterans after they have completed their service. This is a knowledge gap. There are currently unexploited opportunities to learn more about respiratory (and other) health outcomes in theater veterans through the use of data from such sources to significantly expand the number and diversity of study subjects. Such data could be used in case studies, epidemiologic investigations, and so-called big data analyses that take advantage of high-speed, large-capacity empirical methodologies to uncover possibly unexpected relationships between variables. A 2018 National Academies workshop titled Informing Environmental Health Decisions Through Data Integration addressed the utility of this final approach. Chris Gen- nings, the director of the Division of Biostatistics and a research professor in the Department of Environmental Medicine and Public Health at the Icahn School of Medicine at Mount Sinai, noted that big data analysis can be productively applied to both integrate data from disparate study types (such as those linking environmental expo- sures and health outcomes) and to integrate data across epidemiology studies (NASEM, 2018c). The challenge, she observed, is compatibility: whether different data sets should be combined and how to determine if the data integration is done correctly. Potential partnering organizations in addition to TRICARE include private-sector health providers and the Centers for Medicare & Medicaid Services system. It should be noted, though, that significant challenges exist in gaining permission to access medical information and in harmonizing or integrating disparate databases. Partnering will thus require the expenditure of resources, an extended commitment to making health information compatible across systems and providers, and—importantly—compromises from all parties to further the greater good. REFERENCES Abraham, J. H., A. Eick-Cost, L. L. Clark, Z. Hu, C. P. Baird, R. DeFraites, S. K. Tobler, E. E. Richards, J. M. Sharkey, R. J. Lipnick, and S. L. Ludwig. 2014. A retrospective cohort study of military deployment and postdeployment medical encounters for respiratory condition. Military Medicine 176(5):540–546. Aldrich, T. K., J. Gustave, C. B. Hall, H. W. Cohen, M. P. Webber, R. Zeig-Owens, K. Cosenza, V. Christodoulou, L. Glass, F. Al-Othman, and M. D. Weiden. 2010. Lung function in rescue workers at the World Trade Center after 7 years. New England Journal of Medicine 362(14):1263–1272. Alolayan, M. A., K. W. Brown, J. S. Evans, W. S. Bouhamra, and P. Koutrakis. 2013. Source apportionment of fine particles in Kuwait City. Science of the Total Environment 448:14–25. APHC (Army Public Health Command). 2010. Screening health risk assessments: Joint Base Balad, Iraq, 11 May–19 June 2009. Aberdeen Proving Ground, MD: U.S. Army Center for Health Promotion and Preventive Medicine. APHC. 2018. Periodic occupational and environmental monitoring summary (POEMS). https://phc.amedd.army.mil/topics/ envirohealth/hrasm/Pages/POEMS.aspx (accessed April 27, 2020). Aurell, J., B. K. Gullett, and D. Yamamoto. 2012. Emissions from open burning of simulated military waste from forward operating bases. Environmental Science & Technology 46(20):11004–11012. Australian Government DVA (Department of Veterans’ Affairs). 2019. Preliminary Gulf War nominal roll. https://www.dva. gov.au/recognition/events-and-reminders-all-who-served/records-and-military-history/preliminary-gulf-war (accessed May 5, 2020). Barth, S. K., H. K. Kang, and T. Bullman. 2016. All-cause mortality among US veterans of the Persian Gulf War: 13-year follow-up. Public Health Reports 131(6):822–830. Billatos, E., F. Duan, E. Moses, H. Marques, I. Mahon, L. Dymond, C. Apgar, D. Aberle, G. Washko, and A. Spira. 2019. Detection of Early Lung Cancer among Military Personnel (DECAMP) consortium: Study protocols. BMC Pulmonary Medicine 19(1):59. Blasch, K. W., J. E. Kolivosky, and J. M. Heller. 2016. Environmental air sampling near burn pit and incinerator operations at Bagram Airfield, Afghanistan. Journal of Occupational and Environmental Medicine 58(8 Suppl 1):S38–S43. Bollinger, M. J., S. Schmidt, J. A. Pugh, H. M. Parsons, L. A. Copeland, and M. J. Pugh. 2015. Erosion of the healthy soldier effect in veterans of U.S. military service in Iraq and Afghanistan. Population Health Metrics 13(1):8.

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More than 3.7 million U.S. service members have participated in operations taking place in the Southwest Asia Theater of Military Operations since 1990. These operations include the 1990-1991 Persian Gulf War, a post-war stabilization period spanning 1992 through September 2001, and the campaigns undertaken in the wake of the September 11, 2001, attacks. Deployment to Iraq, Kuwait, Saudi Arabia, Bahrain, Gulf of Aden, Gulf of Oman, Oman, Qatar, the United Arab Emirates, and Afghanistan exposed service members to a number of airborne hazards, including oil-well fire smoke, emissions from open burn pits, dust and sand suspended in the air, and exhaust from diesel vehicles. The effects of these were compounded by stressors like excessive heat and noise that are inevitable attributes of service in a combat environment.

Respiratory Health Effects of Airborne Hazards Exposures in the Southwest Asia Theater of Military Operations reviews the scientific evidence regarding respiratory health outcomes in veterans of the Southwest Asia conflicts and identifies research that could feasibly be conducted to address outstanding questions and generate answers, newly emerging technologies that could aid in these efforts, and organizations that the Veterans Administration might partner with to accomplish this work.

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