Development and Validation of the Veteran Military Occupational and Environmental Exposure Assessment Tool.

INTRODUCTION: Military exposures may present a cumulative load and increased individual susceptibility to negative health outcomes. Currently, there are no comprehensive and validated environmental exposure assessment tools covering the full spectrum of occupational and environmental exposures for Veterans. The Veterans Affairs (VA) War Related Illness and Injury Study Center in Washington, DC, developed the Veteran Military Occupational and Environmental Exposure Assessment Tool (VMOAT) to establish a structured, comprehensive self-report tool that captures military and non-military occupational and environmental exposures. The VMOAT is clinically insightful, modular, and flexible for adding novel exposures, meeting the needs of modern evolving threats and exposures in both clinical and research settings. This manuscript reviews the ongoing development and validation plans for the VMOAT. MATERIALS AND METHODS: The VMOAT is a self-reported structured questionnaire, and VMOAT 1.0 was developed to cover an individual's 3 life phases (pre, during, post-military service); 5 exposure domains (chemical, physical, biological, injuries including ergonomic, and psychological stress exposures, plus military preventive health measures); and 64 specific exposures nested within exposure categories. VMOAT 1.0 addresses exposure dose (frequency, duration, proximity, route), and can be administered online via VA approved Qualtrics survey software. VMOAT 1.0 to 2.0 updates began in December 2022 with changes focused on readability, streamlining the exposure history, refining the exposure metrics, and improving the skip logic embedded within the survey design. RESULTS: The initial VMOAT 1.0 development included face and construct validation with expert internal and external academic and military collaborators, undergoing an iterative 5-cycle review as well as sample testing among a small group of Veterans. The VMOAT 1.0 was used in Institutional Review Board (IRB)-approved longitudinal study, which has been examined preliminarily to compare the VMOAT 1.0 with other exposure assessments and to compare responses of Explosive Ordnance Disposal Veterans, a high occupational exposure cohort, to non-Explosive Ordnance Disposal Veterans. Ongoing VMOAT 2.0 updates will include integration of experiences from piloting the VMOAT 1.0 as well as additional face and content validation and survey cognitive testing with Veterans. VMOAT 2.0 data will improve the development of exposure-informed models using composite survey data to create scored- and scale-based exposure metrics for specific exposures and exposure domains. These data will highlight the effectiveness of the VMOAT as a structured comprehensive occupational and environmental exposure assessment instrument. CONCLUSIONS: VMOAT development supports the 2022 Promise to Address Comprehensive Toxics Act and fits into the existing VA exposure assessment approach as a standardized, comprehensive self-reported exposure assessment tool. It can be utilized as a stand-alone instrument or supplemented by clinician interviews in research or specialty evaluation programs. The collected VMOAT self-report information on military occupational and environmental exposures will allow direct evaluation with objective measures of exposure and health outcomes. These data outcomes have a high potential to guide the DoD and VA environmental exposure risk mitigation and risk communication efforts.

Preparedness of Military Public Health for Epidemic and Pandemic Recognition and Response.

Disease epidemics have threatened American military preparedness and operational capabilities since 1775. The ongoing Severe Acute Respiratory Syndrome Coronavirus 2 (COVID-19) pandemic, which began in 2019, again demonstrates the significant potential for infectious diseases to impact military units and threaten military readiness. We reviewed the historical and continuing threats to the U.S. Military from infectious disease outbreaks, as well as changes in U.S. Military capabilities for conducting meaningful surveillance and response. We concluded that a structured review of military public health and preventive medicine capabilities should be conducted to assess the response to the COVID-19 pandemic and determine the capabilities necessary for infectious disease surveillance and response to future threats.

Military Epidemics, Then and Now: Smallpox and COVID-19.

We compared the COVID-19 experience in the first year of the current pandemic in the US with the smallpox experience of the 18th century, focusing on the US military but recognizing civilian and military populations are not separate and distinct. Despite the epidemics being separated by 21/2 centuries and with great advancements in technology having occurred over that time, we observed similarities which led us to several conclusions: • Infectious disease outbreaks will continue to occur and novel agents, naturally occurring or manipulated by humans, will threaten military and civilian populations nationally and globally. • Infectious disease outbreaks can affect both military and civilian populations, persist for long periods, and be catastrophic to military peacetime and wartime operations. • Effective surveillance is a prerequisite for early identification and subsequent meaningful responses to novel and reemerging threat agents and diseases. • Socio-cultural, religious, or political factors may limit the implementation of effective interventions in military or civilian populations. Public health officials must assess impediments to implementation of interventions and develop plans to overcome them.

The Capability Gap in Occupational Health Information Management.

The lack of an integrated approach to data capture, information management, and analysis limits the contribution of occupational and environmental medicine to protecting 2.3 million uniformed and civilian DoD workers. Despite an abundance of military information systems that include the terms "Safety" and "Occupational Health" in their names, none of these systems provide capabilities needed to aggregate and analyze the results of occupational medicine exams, use medical surveillance to mitigate exposure incidents, provide enterprise-level management of occupational medicine services, or comply with privacy and recordkeeping law and regulation. Instead, they provide a patchwork of data that meets most regulatory compliance requirements but fails to achieve the true objectives of occupational health programs. Bridging these capability gaps will improve the occupational health care of the DoD workforce, improve the quality of occupational medicine services, increase public trust in the DoD management of exposure incidents, and potentially generate hundreds of millions of dollars through cost-avoidance on workers' compensation claims and through identification and elimination of non-value-added medical certification exams. The ongoing Military Health System transformation represents a unique opportunity to bridge these long-recognized but persistent capability gaps.

Hazardous Non-Combat Exposures in the U.S. Department of Defense.

Hazardous non-combat exposures are inherent to military service and occur in three settings: installation workplaces, installation environments, and deployment environments. Few military clinicians receive training in how to recognize, assess, and manage patients with these exposures, and systems improvements are needed to support clinicians with respect to exposure recognition and management. This commentary highlights key concepts surrounding military non-combat exposures by discussing three case examples of exposures occurring in each of these settings. In the workplace, well-coordinated, interdisciplinary occupational health teams improve identification of exposure-related illnesses, and these teams may be further supported by the development of automated clinical decision-support systems. Installation environmental exposures are characterized by high perceived risk, uncertainty in estimating actual risk, and a wide range of stakeholders including military family members and individuals in the surrounding community. Recognizing environmental exposure concerns, gathering a thorough environmental exposure history, and practicing exposure risk communication are vital skills to address these situations. During deployments, exposures may initially be perceived as low risk but then become a concern years later. A functional understanding of the capabilities and limitations of exposure monitoring and potential health effects of exposures helps the military clinician effectively communicate potential health risks to line leaders. For any of these exposure settings, service public health centers and OEM specialty leaders and consultants are available for consultation.

The Future of Military Occupational and Environmental Medicine in the Department of Defense.

OBJECTIVE: Transfer of military medical facilities to the Defense Health Agency is transforming the Military Health System. Our objective is to inform this transformation with respect to optimum application of occupational and environmental medicine (OEM) expertise. METHODS: We defined and analyzed the external influences on military OEM practice using a structured framework to identify key drivers. RESULTS: Key drivers are political and economic factors. These may change the size or military/civilian ratio of the specialty. Limited career development pathways should prompt consideration of making OEM a second or combined residency, and military-funded training of civilian physicians may be required. OEM specialist utilization should be reassessed. CONCLUSIONS: OEM is a highly adaptable specialty defined by the needs of its stakeholders. Comprehensive analysis of external influences can ensure that OEM practice remains in step with changing needs.

Training Occupational and Environmental Medicine (OEM) Residents at the Uniformed Services University.

OBJECTIVE: To develop an actionable plan to sustain and improve the quality of the Uniformed Services University of the Health Sciences (USU) Occupational and Environmental Medicine (OEM) Residency Program. METHODS: Program metrics were collected and analyzed to assess strengths, weaknesses, opportunities, and threats (SWOT analysis). RESULTS: Program strengths are stable funding, full-time faculty and large class size. Weaknesses are limited toxicology curriculum, and the lack of complex clinical cases. Opportunities include establishing an OEM referral clinic, collaborating with U.S. Department of Defense (DoD) toxicology programs, aligning OEM research priorities in DoD, and including DoD Civilian physicians in OEM residency training. Threats are Military Health System reorganization, budget, and personnel cuts. CONCLUSIONS: The USU OEM Residency is strong but must be flexible to adjust to personnel, fiscal, and organizational changes. Aggregating the SWOT analyses for all the OEM residency programs may help identify strategies to sustain OEM training in the United States.

Uniformed Services University Occupational and Environmental Medicine Residency Program.

In 2019, the Uniformed Services University of the Health Sciences (USU) F. Edward Hébert School of Medicine celebrated the 30th anniversary of its Occupational and Environmental Medicine (OEM) Residency program. This unique program is among the largest preventive medicine residency programs in the United States. Residents from the US Army, Navy, Air Force, other federal institutions, and the Canadian Forces come to Bethesda, Maryland, to become OEM specialists in a unique training program encompassing both military and civilian OEM settings. This publication describes the historical development and practice of OEM in the military leading to the development of the USU OEM Residency Program, along with the program's past accomplishments and current operation. Finally, the publication explores potential future directions for this relatively small but important preventive medicine specialty in the practice of military medicine, considering the impacts of reorganization of the Military Health System along with the opportunities this reorganization presents for the USU OEM Residency program.

Use of Biomarkers to Assess Environmental Exposures and Health Outcomes in Deployed Troops.

OBJECTIVE: This paper provides an overview of our Military Biomarkers Research Study (MBRS) designed to assess whether biomarkers can be used to retrospectively assess deployment exposures and health impacts related to deployment environmental exposures. METHODS: The MBRS consists of four phases. Phase I was a feasibility study of stored sera. Phase II looks at associations between exposures and biomarkers. Phase III examines relationships of biomarkers and health outcomes, and Phase IV investigates in vitro biomarker changes associated with exposures to chemicals of interest. This paper briefly summarizes work already published and introduces the new reports contained in this supplement. RESULTS: Novel biomarkers were identified. These were associated with deployment exposures. CONCLUSIONS: Significant associations were noted between deployment exposures, microRNA biomarkers and metabolomic biomarkers, and deployment health outcomes.

Advances in Comprehensive Exposure Assessment: Opportunities for the US Military.

OBJECTIVE: Review advances in exposure assessment offered by the exposome concept and new -omics and sensor technologies. METHODS: Narrative review of advances, including current efforts and potential future applications by the US military. RESULTS: Exposure assessment methods from both bottom-up and top-down exposomics approaches are advancing at a rapid pace, and the US military is engaged in developing both approaches. Top-down approaches employ various -omics technologies to identify biomarkers of internal exposure and biological effect. Bottom-up approaches use new sensor technology to better measure external dose. Key challenges of both approaches are largely centered around how to integrate, analyze, and interpret large datasets that are multidimensional and disparate. CONCLUSIONS: Advances in -omics and sensor technologies may dramatically enhance exposure assessment and improve our ability to characterize health risks related to occupational and environmental exposures, including for the US military.

Environmental Chemicals Altered in Association With Deployment for High Risk Areas.

OBJECTIVE: A study was conducted using serum samples and high-resolution metabolomics (HRM) to test for changes in abundance of environmental chemicals in deployment in high-risk areas (Balad, Iraq; Bagram, Afghanistan). METHODS: Pre and Post-deployment serum samples for deployment (cases) and matched controls stationed domestically were analyzed by HRM and bioinformatics for the relative abundance of 271 environmental chemicals. RESULTS: Of the 271 chemicals, 153 were measurable in at least 80% of the samples in one of the pre- or post-deployment groups. Several pesticides and other chemicals were modestly elevated post-deployment in the Control as well as the Bagram and Balad samples. Similarly, small decreases were seen for some chemicals. CONCLUSION: These results using serum samples show that for the 271 environmental chemicals studied, 56% were detected and small differences occurred with deployment to high-risk areas.

Metabolome-Wide Association Study of Deployment to Balad, Iraq or Bagram, Afghanistan.

OBJECTIVE: To use high-resolution metabolomics (HRM) to identify metabolic changes in military personnel associated with deployment to Balad, Iraq, or Bagram, Afghanistan. METHODS: Pre- and post-deployment samples were obtained from the Department of Defense Serum Repository (DoDSR). HRM and bioinformatics were used to identify metabolic differences associated with deployment. RESULTS: Differences at baseline (pre-deployment) between personnel deployed to Bagram compared with Balad or Controls included sex hormone and keratan sulfate metabolism. Deployment to Balad was associated with alterations to amino acid and lipid metabolism, consistent with inflammation and oxidative stress, and pathways linked to metabolic adaptation and repair. Difference associated with deployment to Bagram included lipid pathways linked to cell signaling and inflammation. CONCLUSIONS: Metabolic variations in pre- and post-deployment are consistent with deployment-associated responses to air pollution and other environmental stressors.

Associations of Benzo(ghi)perylene and Heptachlorodibenzo-p-dioxin in Serum of Service Personnel Deployed to Balad, Iraq, and Bagram, Afghanistan Correlates With Perturbed Amino Acid Metabolism in Human Lung Fibroblasts.

OBJECTIVE: A study was conducted to identify metabolic-related effects of benzo(ghi)perylene (BghiP) and 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD), on primary human fibroblasts to verify biological associations previously found in occupational health research. METHODS: Human lung fibroblasts were exposed to BghiP or HpCDD and extracts were analyzed with a metabolome-wide association study to test for pathways and metabolites altered relative to controls. Gene expression was measured by quantitative-real time polymerase chain reaction. RESULTS: Metabolic perturbations in amino-acid, oxidative stress, and fatty-acid pathways were observed for BghiP and HpCDD. HpCDD but not BghiP exposure increased gene expression of the amino acid transporters SLC7A5 and SLC7A11. CONCLUSIONS: Exposure to polycyclic aromatic hydrocarbons (PAH) or dioxins perturbs amino acid pathways at physiologically relevant concentrations with different mechanisms. These findings imply an effect on central homeostatic systems by environmental exposures which could have implications on disease susceptibility.

Analysis of Postdeployment Serum Samples Identifies Potential Biomarkers of Exposure to Burn Pits and Other Environmental Hazards.

OBJECTIVE: The potential health risks of deployment to sites with open burn pits remain poorly understood, in part, because personal exposure monitoring was not performed. Here, we investigated whether postdeployment serum samples contain biomarkers associated with exposure to burn pits. METHODS: A total of 237 biomarkers were measured in 800 serum samples from deployed and never-deployed subjects. We used a regression model and a supervised vector machine to identify serum biomarkers with significant associations with exposures and deployment. RESULTS: We identified 101 serum biomarkers associated with polycyclic aromatic hydrocarbons, dioxins or furans, and 54 biomarkers associated with deployment. Twenty-six of these biomarkers were shared in common by the exposure and deployment groups. CONCLUSIONS: We identify a potential signature of exposure to open burn pits, and provide a framework for using postexposure sera to identify exposures when contemporaneous monitoring was inadequate.

Machine Learning Approach for Predicting Past Environmental Exposures From Molecular Profiling of Post-Exposure Human Serum Samples.

OBJECTIVE: To develop an approach for a retrospective analysis of post-exposure serum samples using diverse molecular profiles. METHODS: The 236 molecular profiles from 800 de-identified human serum samples from the Department of Defense Serum Repository were classified as smokers or non-smokers based on direct measurement of serum cotinine levels. A machine-learning pipeline was used to classify smokers and non-smokers from their molecular profiles. RESULTS: The refined supervised support vector machines with recursive feature elimination predicted smokers and non-smokers with 78% accuracy on the independent held-out set. Several of the identified classifiers of smoking status have previously been reported and four additional miRNAs were validated with experimental tobacco smoke exposure in mice, supporting the computational approach. CONCLUSIONS: We developed and validated a pipeline that shows retrospective analysis of post-exposure serum samples can identify environmental exposures.

Integrative Network Analysis Linking Clinical Outcomes With Environmental Exposures and Molecular Variations in Service Personnel Deployed to Balad and Bagram.

OBJECTIVE: To develop a computational approach to link clinical outcomes with environmental exposures and molecular variations measured in Department of Defense (DOD) serum-repository samples. METHODS: International Classification of Diseases, Ninth Division codes which corresponded to cardiopulmonary symptoms for service personnel were selected to test for associations with deployment-related inhalation hazards and metabolomics, micro-RNA, cytokine, plasma markers, and environmental exposure analyses for corresponding samples. xMWAS and Mummichog were used for integrative network and pathway analysis. RESULTS: Comparison between 41 personnel exhibiting new cardio-pulmonary diagnoses after deployment start-date to 25 personnel exhibiting no symptoms identified biomarkers associated with cardiopulmonary conditions. Integrative network and pathway analysis showed communities of clinical, molecular, and environmental markers associated with fatty acid, lipid, nucleotide, and amino acid metabolism pathways. CONCLUSIONS: The current proof of principle study establishes a computational framework for integrative analysis of deployment-related exposures, molecular responses, and health outcomes.

Benzo[a]pyrene Perturbs Mitochondrial and Amino Acid Metabolism in Lung Epithelial Cells and Has Similar Correlations With Metabolic Changes in Human Serum.

OBJECTIVE: A study was conducted to identifymetabolic-related effects of benzo[a]pyrene (BaP) on human lung epithelial cells and validate these findings using human sera. METHODS: Human lung epithelial cells were treated with BaP, and extracts were analyzed with a global metabolome-wide association study (MWAS) to test for pathways and metabolites altered relative to vehicle controls. RESULTS: MWAS results showed that BaP metabolites were among the top metabolites differing between BaP-treated cells and controls. Pathway enrichment analysis further confirmed that fatty acid, lipid, and mitochondrial pathways were altered by BaP. Human sera analysis showed that lipids varied with BaP concentration. BaP associations with amino acid metabolism were found in both models. CONCLUSIONS: These findings show that BaP has broad metabolic effects, and suggest that air pollution exacerbates disease processes by altered mitochondrial and amino acid metabolism.

Exposure to Heptachlorodibenzo-p-dioxin (HpCDD) Regulates microRNA Expression in Human Lung Fibroblasts.

OBJECTIVE: Benzo(ghi)perylene (BghiP) and 1,2,3,4,6,7,8-Heptachlorodibenzo-p-dioxin (HpCDD) were elevated in serum from personnel deployed to sites with open burn pits. Here, we investigated the ability of BghiP and HpCDD to regulate microRNA (miRNA) expression through the aryl hydrocarbon receptor (AHR). METHODS: Human lung fibroblasts (HLFs) were exposed to BghiP and HpCDD. AHR activity was measured by reporter assay and gene expression. Deployment related miRNA were measured by quantitative polymerase chain reaction. AHR expression was depleted using siRNA. RESULTS: BghiP displayed weak AHR agonist activity. HpCDD induced AHR activity in a dose-dependent manner. Let-7d-5p, miR-103-3p, miR-107, and miR-144-3p levels were significantly altered by HpCDD. AHR knockdown attenuated these effects. CONCLUSIONS: These studies reveal that miRNAs previously identified in sera from personnel deployed to sites with open burn pits are altered by HpCDD exposure in HLFs.

Systematic review of military motor vehicle crash-related injuries.

CONTEXT: Motor vehicle crashes account for nearly one third of U.S. military fatalities annually. The objective of this review is to summarize the published evidence on injuries due specifically to military motor vehicle (MMV) crashes. EVIDENCE ACQUISITION: A search of 18 electronic databases identified English language publications addressing MMV crash-related injuries between 1970 and 2006 that were available to the general public. Documents limited in distribution to military or government personnel were not evaluated. Relevant articles were categorized by study design. EVIDENCE SYNTHESIS: The search identified only 13 studies related specifically to MMV crashes. Most were case reports or case series (n=8); only one could be classified as an intervention study. Nine of the studies were based solely on data from service-specific military safety centers. CONCLUSIONS: Few studies exist on injuries resulting from crashes of military motor vehicles. Epidemiologic studies that assess injury rates, type, severity, and risk factors are needed, followed by studies to evaluate targeted interventions and prevention strategies. Interventions currently underway should be evaluated for effectiveness, and those proven effective in the civilian community, such as graduated driver licensing, should be considered for implementation and evaluation in military populations.