The Respiratory Effects of Jet Fuel Exposure

In combination, evidence from epidemiological and toxicological studies indicates that jet fuel exposure may result in adverse respiratory effects. This information may help clinicians guide patients to reduce exposures or inform screening for early disease.

Abstract

Objective

Jet fuel inhalation represents one of the most significant exposures among service members; however, health outcomes are unclear, and the processes linking exposures and respiratory effects are undefined.

Methods

A systematic literature review of human, animal, and mechanistic studies was conducted to assess and synthesize the scientific evidence on the adverse respiratory effects of jet fuel exposure.

Results

Animal studies provided moderate evidence that jet fuel inhalation resulted in adverse effects through cytotoxicity, tissue damage, inflammation, airway remodeling, and lung function changes, which was corroborated by mechanistic data. This was further supported by slight epidemiologic evidence that jet fuel exposure is associated with increased respiratory symptoms and disease.

Conclusions

Evidence indicates that jet fuel exposure is likely to produce adverse respiratory effects, which may have important implications for exposed service members and veterans.

LEARNING OUTCOMES

• Upon reviewing this manuscript, readers will be able to comprehensively describe the state of the scientific literature on the respiratory health effects associated with exposure to jet fuels used by the U.S. military.

• Upon reviewing this manuscript, readers will be able to summarize the epidemiologic and animal toxicological evidence of jet fuel exposure-related health outcomes associated with respiratory tissue damage, inflammation, lung remodeling, and lung function.

• Upon reviewing this manuscript, readers will be able to evaluate concordance between available epidemiologic, animal toxicological, and mechanistic data to identify data gaps for future research.

In 2022, over 2 million men and women served in the US military on active-duty or as members of the National Guard or Reserves according to the Department of Defense.¹ Although these individuals must meet stringent health and fitness standards to join and remain in service, data collected between 2003 and 2019 indicated that US veterans often have higher morbidity rates compared to the general population.² It is also well established that military service may put individuals at risk of exposure to a myriad of environmental hazards that could impact long-term health.^3,4 Further, military personnel are exposed to several environmental stressors, such as extreme heat,⁵ loud noise,⁶ psychological stress,⁷ smoking,⁸ and crowded living and working conditions⁹ that could further increase their susceptibility to adverse health effects following military environmental exposures.

Respiratory health is particularly at risk for service members, as many environmental hazards are inhaled. Veterans who deployed to regions like Southwest Asia^10–12 are known to experience a variety of respiratory conditions, including allergic rhinitis,¹³ chronic obstructive pulmonary disease (COPD),^13–15 asthma and chronic airway obstruction,^13,15,16 chronic sinusitis,¹³ and lung cancer.^10,13,14 The prevalence of some conditions often escalates after the age of 60 years.¹⁴

Environmental stressors can result in inflammation of the respiratory tissues.¹⁷ Persistent respiratory tract inflammation has been linked with the progression of chronic respiratory conditions.^18,19 For certain conditions, such as COPD, repeated exacerbations of respiratory symptoms or infections over time can contribute to decreased lung function and disease progression.^20,21

To adequately protect the health of military personnel and veterans, the relationships between hazardous exposures and adverse respiratory outcomes must be better understood. Studies evaluating exposures to various hazards related to military service, such as Agent Orange²² and burn pits,¹⁰ have established associations with certain respiratory conditions. However, military personnel may also be exposed to other hazards that target the respiratory system, such as jet fuels. These fuels are commonly used in military operations and contain volatile chemical mixtures and particulate matter that, upon combustion, can be inhaled during routine tasks.⁴ Although there are policies in place regarding personal protective equipment (PPE) to be worn for certain occupations, adherence to those policies and effective use of PPE are unknown.²³ Further, environmental exposure via potable water contaminated with jet fuels may pose a hazard to military personnel and their families; such contamination has occurred at the Red Hill Bulk Fuel Storage Facility near Joint Base Pearl Harbor-Hickam, Hawaii, and at Camp Lejeune, North Carolina.^24,25

Prior reviews on the respiratory effects associated with exposure to jet fuels have reported mixed results from animal studies. One review reported respiratory inflammation and altered pulmonary function,⁴ and another reported no effects.²⁶ Few human studies have focused on this issue, highlighting a critical gap in knowledge.^4,26 A follow-up review concluded that, despite mixed findings in animal studies, the respiratory system appeared vulnerable to Jet Propellent-8 (JP-8) exposure based on case reports and effects observed following exposure to kerosene, the major component of most jet fuels used by the military.²⁷

The following systematic review aims to build on the findings from a previous review conducted by VA,²⁸ integrating data from multiple evidence streams to comprehensively assess the health impacts of jet fuel exposure. This includes occupational and environmental exposure evidence in humans, as well as the available animal and mechanistic evidence related to respiratory effects associated with jet fuel exposure. Evidence was identified, evaluated, and synthesized using an established framework to gain a better understanding of the potential long-term impact of jet fuel exposure and the health care needs of veterans who may have been impacted by jet fuel exposure during their service.

METHODS

To expand upon the previously conducted literature search on jet fuel exposure in military and occupationally exposed persons, this systematic literature review was designed to capture evidence from epidemiologic (both occupational and environmental exposures), animal toxicological, and mechanistic studies.²⁸ This review relied on methods outlined by the US Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) assessment framework^29,30 to conduct comprehensive assessments of the scientific evidence and support evaluation of the effects of chemical agents. The following subsections briefly summarize the methods used to identify, screen, and evaluate the literature on jet fuel exposure and respiratory effects. The systematic review methodology is comprehensively detailed in Bergeron et al.³¹

Literature Search Strategy

The Populations, Exposures, Comparators, and Outcomes (PECO) criteria guided the development of search terms and the strategy to identify epidemiologic, animal toxicological, and mechanistic references. Literature searches to identify relevant studies were conducted through March 2025. Four types of data sources were reviewed to compile the list of references for this assessment: scientific literature databases (PubMed and EBSCOhost), gray literature sources, subject matter expert-identified publications, and relevant epidemiologic and animal toxicological references cited in secondary data sources.

Inclusion and Exclusion Criteria

The review was formulated using PECO frameworks to guide the literature search and screening processes, including the inclusion or exclusion of studies. Briefly, the review focused on humans or vertebrates of any life stage or ex vivo/in vitro samples or in silico models (Population) exposed to jet fuels (Exposure) compared to groups with no or lower exposure levels (Comparator) reporting any respiratory health effects or any respiratory health–related cellular, biochemical, or molecular changes (Outcome). Studies assessing exposure to jet fuel or its complete combustion products were considered relevant, whereas studies restricted to exposure of isolated jet fuel components (eg, exhaust gaseous components or exhaust particles) were excluded. Case reports, case studies, case series, and secondary data sources were considered supplemental information for this review. These sources of information did not contribute to the weight-of-evidence determinations but were considered during the evidence synthesis.

Literature Screening and Data Extraction

To determine PECO relevance during title/abstract and full-text screening, two independent reviewers screened each reference, and only references that passed title/abstract screening went to full-text screening. In cases of nonconcurrence between the reviewers, conflict resolution was conducted by a subject-matter expert in epidemiology or toxicology. Studies screened and found to be not PECO-relevant did not undergo study quality evaluation or data extraction.

During the screening process, overlapping and partially overlapping datasets were identified. An overlapping dataset was considered as a set of publications reporting results from the same epidemiologic or animal toxicological study population. In contrast, a partially overlapping dataset included a set of references reporting on the same animals in multiple publications but with distinct endpoints. To ensure accuracy when reporting the number of unique references, overlapping datasets were not considered independently in the evidence synthesis; however, partially overlapping datasets were, as they reported on different endpoints.

All relevant human epidemiologic, animal toxicological, and mechanistic studies underwent data extraction to identify and compile all potentially relevant study details and results. An initial reviewer conducted the extraction, then a second reviewer confirmed the accuracy of the extracted data. All health endpoints were extracted regardless of magnitude of effect, statistical significance, or quality of the study. Only qualitative information was extracted from case reports, case studies, case series, secondary reviews, and mechanistic studies.

Study Quality Evaluation

Evaluations were conducted by a primary reviewer, followed by a senior quality assurance reviewer (a deviation from the IRIS approach), who assigned a rating on the reliability of the study for each study quality domain as described in the IRIS Handbook.³⁰ The individual domains were rated as good, adequate, deficient, not reported (an animal toxicological-specific rating that could carry the same functional interpretation as adequate or deficient), or critically deficient. The two reviewers evaluated the strengths and limitations of each study to reach an overall determination on study confidence of high, medium, low, or uninformative.³⁰ Any disagreements between reviewers were discussed with the evaluation team or a subject matter expert. The overall confidence rating reflects a summary interpretation of the potential influence of study limitations on the direction and/or magnitude of the results. Study quality ratings were determined for each endpoint; within a study, it was possible for endpoints to have different confidence ratings, resulting in multiple judgments for a single study. Study quality evaluation was not conducted on case reports, case studies, case series, secondary reviews, overlapping references, or mechanistic studies. The study quality evaluation rationales are available in an interactive Tableau dashboard in the study quality evaluation heatmap https://public.tableau.com/app/profile/vha.home/viz/SupportingInformationforVHAJetFuelsReport_17002413903760/ReadMe?publish=yes.

Evidence Synthesis and Integration

The overall study confidence was considered when synthesizing epidemiologic and animal toxicological health effect evidence. For each evidence stream, strength-of-evidence judgments were made by subject-matter experts focused on the evaluation of several factors, including study quality, consistency and coherence of scientific findings across studies, dose-response relationships, strength of association, and outcome directness. During evidence synthesis and determination of the strength-of-evidence judgments, results from high and medium confidence studies were given priority over low confidence studies (epidemiologic and animal toxicological) and uninformative studies (considered in epidemiologic studies only, given the limited quantity and quality of the available literature). Strength-of-evidence judgments used standard terminology (ie, robust, moderate, slight, indeterminate, and compelling evidence of no effect), as outlined within the IRIS Handbook,³⁰ which adapts Hill's causality criteria.³²

Evidence integration judgments were developed through a comprehensive review of epidemiologic and animal toxicological evidence, with consideration of various factors, such as the relevance of animal toxicological findings to human health, data consistency within and across evidence streams, sensitivity to susceptible populations, biological plausibility and mode of action, and mechanistic evidence to aid in determining biological plausibility. Mechanistic data were applied as supporting evidence to better understand potential human health outcomes. Standard terminology (eg, evidence demonstrates, evidence indicates (likely), evidence suggests, evidence inadequate, or strong evidence supports no effect), as outlined within the IRIS Handbook,³⁰ was utilized.

RESULTS

Literature Search and Study Selection

The results of the study identification process are provided in Figure 1. A total of 4291 references were identified, of which 621 were relevant after title/abstract screening. Following full-text evaluation, 279 references met the inclusion criteria, consisting of 42 epidemiologic references, 125 animal toxicological references, and 113 mechanistic references. A total of 119 references focused on respiratory health outcomes, with 10 primary epidemiologic references, 55 animal toxicological references, and 26 mechanistic references. A Tableau dashboard provides all information on the relevant literature and study quality, including a diagram using the Interactive REFerence Flow (I-REFF) approach to provide transparency and traceability of references,³³ epidemiologic and animal toxicological study quality evaluation heatmaps with overall confidence score rationales, and epidemiologic, animal toxicological, and mechanistic study evidence maps. All data utilized within the interactive visuals are available for download at: https://public.tableau.com/app/profile/vha.home/viz/SupportingInformationforVHAJetFuelsReport_17002413903760/ReadMe?publish=yes.

FIGURE 1.

Reference flow diagram of the search, screening, and selection of respiratory system health outcome studies included in the review. This figure provides an overview of the study identification process results. The literature search yielded 4291 references. After completing title and abstract screening and full-text screening, 279 references were deemed relevant, with 42 epidemiologic references and 125 animal toxicological references. Of the 279 total relevant references, 119 specifically discussed respiratory effects of jet fuel exposure, including 10 epidemiologic references, six case reports or case series, 55 animal toxicological references, 26 mechanistic references, and 22 secondary data sources. ^aA study may have reported on multiple model types; therefore, the total for the category was greater than the total relevant references. ^bSix references reported on the same epidemiologic study. After accounting for multiple references, there were 36 unique epidemiologic studies in this body of literature. ^cSeven references reported on the same animal toxicological study. Seven references were classified as partial overlaps as they reported on a portion of the same health outcome endpoints as another reference; however, unique endpoints reported were considered individually. After accounting for multiple references, there were 118 unique animal toxicological studies in this body of literature. ^dEleven references reported on the same animal toxicological study of respiratory health outcomes. Three additional references were classified as partial overlap as they reported on a portion of the same respiratory endpoints as another reference; however, all other respiratory endpoints reported were unique. After excluding reports of the same data, there were 44 unique animal toxicological studies in this body of literature.

Of the 10 primary epidemiologic studies assessing the association between jet fuel exposure and respiratory outcomes, one was considered medium confidence, four were low confidence, and five were uninformative (Fig. 2). No epidemiologic studies were considered high confidence. Concerns identified in studies that were considered low confidence or uninformative included potential selection bias, exposure misclassification due to measurement methods, outcome misclassification due to the use of self-reported symptoms or disease, potential for residual confounding, and limited study sensitivity.

FIGURE 2.

Summary of study quality evaluation results for respiratory health outcomes for epidemiologic studies of jet fuel exposure. This heatmap provides an overview of the study quality ratings assigned to the 10 epidemiologic studies that reported respiratory effects following jet fuel exposure. The validity and utility of each study were assessed based on potential bias related to participant selection, exposure measurement, outcome ascertainment, potential confounding, analysis, selective reporting, and study sensitivity. The evaluation domain rating (eg, good, adequate, deficient, critically deficient) and overall study confidence classification (eg, high, medium, low, uninformative) were determined by primary and secondary reviewers for each study. Domain ratings and overall study confidence classifications were based on descriptions outlined in Section 4.1.1 of the IRIS Handbook³⁰ and are further discussed in Bergeron et al.³¹ One study was considered medium confidence, four studies were considered low confidence, and five studies were considered uninformative.

Forty-four unique animal toxicological studies were identified that examined the association between respiratory health outcomes and jet fuel exposure (Fig. 3). Study quality evaluations identified two high confidence, two mixed confidence (high/medium), one mixed confidence (high/low), nine medium confidence, six mixed confidence (medium/low), one mixed confidence (medium/low/uninformative), one mixed confidence (medium/uninformative), 15 low confidence, one mixed confidence (low/uninformative), and six uninformative studies. Studies that were identified as low confidence or uninformative contained one or more of the following issues: lack of clarity during reporting, lack of details on how animals were allocated to exposure groups, observational biases, confounding variables, high levels of attrition, lack of sensitivity and/or specificity of endpoint measurements, or lack of detailed results that reduced the ability to interpret findings. Uninformative animal toxicological studies were excluded from further analysis and were not included in the synthesis.^34–38 One study was uninformative for animal toxicological endpoints but contained relevant mechanistic data.³⁹

FIGURE 3.

Summary of study quality evaluation results for respiratory health outcomes for animal toxicological studies of jet fuel exposure. This heatmap provides an overview of the study quality ratings assigned to the 44 animal toxicological studies that reported respiratory effects following jet fuel exposure. Study quality ratings were created by first assessing individual domains and then combining scores to produce an overall confidence rating. The validity and utility of each study were assessed based on potential bias related to reporting; allocation; observational bias and blinding; confounding variables; reporting and attrition; chemical administration and characterization; exposure timing, frequency, and duration; endpoint sensitivity and specificity; and results presentation. The evaluation domain rating (eg, good, adequate, deficient, critically deficient) and overall study confidence classification (eg, high, medium, low, uninformative) were determined by primary and secondary reviewers for each study. Domain ratings and overall study confidence classifications were based on descriptions outlined in Section 4.1.1 of the IRIS Handbook³⁰ and are further discussed in Bergeron et al.³¹ Of the 44 studies, 2 were considered high confidence, two were considered mixed confidence (high/medium), 1 was considered mixed confidence (high/low), 9 were considered medium confidence, 6 were considered mixed confidence (medium/low), 1 was considered mixed confidence (medium/low/uninformative), 1 was considered mixed confidence (medium/uninformative), 15 were considered low confidence, 1 was considered mixed confidence (low/uninformative), and 6 were considered uninformative studies. ^aBogo et al⁴⁰ had a partially overlapping dataset with Parker et al⁴¹ for some respiratory health outcomes; therefore, this paper underwent study quality evaluation for unique respiratory health outcomes only. ^bMacEwen and Vernot^42–47 reported overlapping datasets with Kinkead et al,^48,49 Bruner et al,⁵⁰ Mattie et al,⁵¹ Newton et al,⁵² Gaworksi et al,⁵³ MacEwen and Vernot,³⁴ and Haun et al⁵⁴ for all respiratory health outcomes; therefore, these papers did not undergo study quality evaluation. ^cMacEwen and Vernot³⁴ had a partially overlapping dataset with Kinkead et al,^48,49 Bruner et al,⁵⁰ Gaworksi et al,⁵³ Mattie et al,⁵¹ and Newton et al⁵² for some respiratory health outcomes; therefore, this paper underwent study quality evaluation for unique respiratory health outcomes only. ^dNordholm et al⁵⁵ had an overlapping dataset with MacMahon et al⁵⁶ for all respiratory health outcomes; therefore, this paper did not undergo study quality evaluation. ^eDodd⁵⁷ had an overlapping dataset with MacMahon et al⁵⁶ and Wolfe et al³⁵ for all respiratory health outcomes; therefore, this paper did not undergo study quality evaluation. ^fMattie et al⁵⁸ had an overlapping dataset with Sterner et al⁵⁹ for all respiratory health outcomes; therefore, this paper did not undergo study quality evaluation. ^gMattie et al⁶⁰ had an overlapping dataset with Sterner et al⁶¹ for all respiratory health outcomes; therefore, this paper did not undergo study quality evaluation. ^hSterner et al⁶² had a partially overlapping dataset with Wong et al⁶³ for some respiratory health outcomes; this paper underwent study quality evaluation for unique respiratory health outcomes only.

Processes and Mechanisms of Jet Fuel Effects

Epidemiologic, animal toxicological, and mechanistic studies provide critical insight into highly interlinked biological processes that mediate respiratory effects following jet fuel exposure (Fig. 4). During inhalational exposure, jet fuel comes into direct contact with airway tissues. Animals that inhaled jet fuel through whole-body or nose-only exposure exhibited molecular and histological evidence of respiratory tract cytotoxicity and tissue damage. Additionally, alternative exposure routes, such as oral,^41,64 dermal,^65,66 and aquatic (via rearing water),^67,68 were included in the study characteristic tables if respiratory related endpoints were assessed but were not discussed in the results text below. Overall, the findings from these studies point toward a pathway of tissue damage and inflammation, leading to airway remodeling and changes in pulmonary function that can ultimately culminate in respiratory symptoms and disease.

FIGURE 4.

Proposed mechanistic pathways linking jet fuel inhalation exposure with respiratory symptoms and disease. Evidence from this systematic review and supporting literature suggest that inhalation of jet fuel induces adverse effects on airway epithelium cellular processes, resulting in subsequent lung function changes and respiratory symptoms and disease. Jet fuel interacts with cellular components within the airway epithelium, resulting in reactive oxygen species formation, activation of molecular effectors of apoptosis, and ultimately cellular injury and death. Damaged and apoptotic cells release intracellular components such as LDH, NAG, and others that may be recognized by immune and airway epithelial cells as DAMPs. This may to the release of proinflammatory mediators that help recruit and activate immune cells, such as macrophages and neutrophils, and promote vasodilation and edema. Repeated episodes of tissue damage and chronic inflammation can lead to airway remodeling, which in jet fuel exposures may include thickening of the airway epithelium, increases in secretory cells in the upper airway (goblet cells) and lower airway (type II cells), fibrosis, and vascular remodeling. These processes may result in lung functional changes and respiratory symptoms and disease. JP-8, jet propellant 8; LDH, lactate dehydrogenase; NAG, N-acetylglucosaminidase; DAMPs, damage-associated molecular patterns; IL-6, interleukin 6; IL-8, interleukin 8; IL-1α, interleukin 1-alpha; IL-1 β, interleukin 1-beta; MYH7, myosin heavy-chain polypeptide 7; SNCG, γ-synuclein; NF-κB, nuclear factor kappa B; AAT, alpha1–ant-trypsin.

Tissue Damage

Jet fuel–induced cellular injury and tissue damage were assessed in animal studies that implemented ultrastructural examination, lung permeability assessments, and histopathologic evaluations (Supplemental Digital Content, Table S1, http://links.lww.com/JOM/C380). Ultrastructural analysis employs high-powered microscopy to assess morphologic changes within individual cells. Ultrastructural examination of jet fuel–exposed lower respiratory tract tissue revealed signs of cellular injury or stress, such as enlarged organelles,^68–71 increased vacuolization,^{68–70,72–75} membrane blebbing,^68–70,76 damaged microvilli,^68,71,76 and changes in lamellar (mucin-containing) bodies.^68–75

At a cell-specific level, several studies revealed that certain populations of airway epithelial cells were more susceptible to injury; however, the cell type and location varied by jet fuel type. For example, Wong et al⁶⁹ demonstrated that short-term JP-8 inhalation damaged the deepest part of the lungs, the alveoli, and terminal bronchioles, specifically the type II alveolar epithelial cells and club cells. However, octasulfur (S-8) at the same concentration did not cause significant effects in this region. Instead, S-8 injury predominantly occurred just above the alveoli in the small airways (bronchiolar area), particularly in club cells. The relative sensitivity of bronchiolar club cells to S-8 was confirmed in another study that observed club cell toxicity at lower concentrations and alveolar type II cell injury only at higher concentrations.⁷⁰

Cellular damage and cytotoxicity can ultimately lead to physiological changes in airway function. A healthy pulmonary epithelium acts as a barrier to the absorption of inhaled chemicals or particles deposited on the lining of the epithelium. When the epithelium is damaged, this barrier is eroded, and the permeability of the airway increases. In animal studies, increased permeability was quantified by measuring the clearance of a radioisotope tracker (technetium-labeled diethylenetriamine pentaacetate, ^99mTc-DTPA). Eight of 10 studies in rats and mice observed that exposure to both JP-8^{70–74,76–78} and S-8⁷⁰ increased the clearance of this tracker (Supplemental Digital Content, Table S1, http://links.lww.com/JOM/C380), thus demonstrating that jet fuel inhalation damages the epithelial airway barrier.

Histopathological examination of airway tissues following jet fuel inhalation revealed signs of tissue damage in the upper and lower respiratory tract in 19 out of 28 studies (Supplemental Digital Content, Table S1, http://links.lww.com/JOM/C380). Tissue damage was typically dose dependent and characterized in pathologic findings as degeneration,^{50,54,59,62,63,71,76,79,80} necrosis,^70,72,74 the sloughing or exfoliation of damaged/dead tissue,^{48,69,71–73,75,78} or hemorrhage.^71,73,74,76 In the lower respiratory tract, the alveoli and bronchiolar spaces were the most frequently affected. Several studies noted adverse changes to the delicate honeycomb architecture of the alveoli that could be attributed to damage and/or inflammation, such as areas of abnormal enlargement (ectasia) or collapse (atelectasis).^72,73,78 In the upper respiratory tract, nasal epithelial degeneration was frequently observed in exposed rats and mice, especially following synthetic fuel exposures.^{50,54,59,62,63,71,76,79,80} Olfactory rosette degeneration was also observed in jet fuel–exposed fish.⁶⁷ Four inhalational studies reported no exposure-related adverse effects in rodents following exposure to JP-8^51,81,82 or JP-5.⁴⁰

Observations of tissue damage were consistent with various mechanistic endpoints (Supplemental Digital Content, Table S2, http://links.lww.com/JOM/C381). Mechanistic data suggest that jet fuel–associated cytotoxicity,⁸³ and cellular injury may be mediated by cellular stress and loss of cell membrane integrity. Bronchoalveolar lavage fluid (BALF) collected from the airways of exposed animals contained increased intracellular components and damage-associated biomolecules, such as lactate dehydrogenase (LDH), N-acetylglucosaminidase (NAG), and elevated total protein levels.^72–74 Jet fuel exposure has been shown to activate molecular effectors of apoptosis, such as poly(ADP-ribose) polymerase-1 (PARP-1) and caspase-3, which may in turn deplete glutathione levels, in both rat lung alveolar macrophages (NR8383 cells) and alveolar epithelial cells (RLE-6TN).^84–88 Furthermore, in an ex vivo study using precision-cut rat lung slices, ultrastructural evaluation identified focal areas of alveolar-septal thickening following 24 hours of exposure to JP-8, indicating alveolar injury.⁸⁹ Ultrastructural damage was also noted via proteomic analysis of whole lung tissue from mice exposed to JP-8 for 1 h/d for 7 days.⁹⁰

As exposure effects can vary over time, results were also assessed in a temporal context. Only three studies were designed to evaluate the effects of tissue damage over time by examining ultrastructural morphology, histopathology, and/or lung permeability after 7 and 28 days of exposure⁸² or 7, 28, and 56 days of exposure^71,76 to JP-8. Both studies examining lung permeability observed increases after 7 and 28 exposure days^71,82; however, after 56 days of exposure, lung permeability returned to control levels.⁷¹ After examination of electron micrographs, the authors attributed this reversal to the deposition of fibrotic tissue reinforcing damaged areas in the lung rather than a recovery of the alveolar-capillary barrier.⁷¹

To examine exposure effects by duration across studies, endpoints related to tissue damage, including lung permeability, BALF endpoints, and histopathology (Supplemental Digital Content, Table S1, http://links.lww.com/JOM/C380, and Supplemental Digital Content, Table S2, http://links.lww.com/JOM/C381), were stratified according to exposure duration and depicted in Figure 5. Across studies, the most severe indications of tissue damage (ie, ectasia, atelectasis, hemorrhage) were all noted in acute/short-term exposures of 1 to 7 days. In subchronic and chronic exposure studies, the most common finding was degeneration of nasal tissue, with tissue damage descriptions decreased in severity.

FIGURE 5.

Respiratory health effects in inhalational animal toxicological studies by duration of jet fuel exposure. A heatmap was created to identify critical data gaps and better understand the link between exposure duration and respiratory effects. Animal exposure endpoints were stratified into acute, short term, subchronic, chronic study designs, and jet fuel type. The number of instances in which adverse effects were observed and the total number of endpoints considered are indicated within each cell, with shading corresponding to the proportion of positive findings. Data gaps are indicated by the dotted lines. The persistence of effects was also examined after recovery periods lasting from 1 to 180 days. Tissue damage endpoints included measurements of lung permeability and markers of tissue damage in bronchoalveolar lavage fluid (BALF), such as lactate dehydrogenase (LDH), N-acetylglucosaminidase (NAG), and total protein. Studies were considered to have positive histopathological or morphometric indicators of tissue damage if they included descriptions of cellular stress (eg, membrane blebbing, lamellar body changes) or processes such as necrosis, degeneration, sloughing or exfoliation of damaged/dead tissue, hemorrhage, or damage to alveolar structures. Indicators of inflammation included studies documenting increased leukocytes in BALF and histological narratives describing the increased presence of inflammatory cells within airway tissues and/or the presence of edema/congestion. Evidence of airway remodeling consisted of histopathology reports of thickened airway epithelium, hypertrophy or hyperplasia of secretory cells, fibrosis/fibrotic processes, or alteration in pulmonary vasculature. Lung weight and lung function changes were obtained from quantitative laboratory experiments. Within each cell, the number of studies reporting at least one adverse treatment related effect is indicated by the numerator and the total number of studies examining the given endpoints is indicated by the denominator. Shading is proportional to the ratio of positive versus total studies.

To assess the persistence of adverse effects, findings from a single identified study that included a recovery period were analyzed. Sweeney et al evaluated markers of tissue damage following 14 days of recovery and reported persistent effects in LDH in BALF and nasal lavage fluid (NALF) after 7 days.⁹¹ Total protein was also elevated in BALF after exposure, suggesting that tissue damage effects may persist for at least 2 weeks.

Inflammation

Jet fuel animal exposure studies that interrogated inflammation processes within the lungs identified that increased presence of inflammatory cells in BALF,^71,72,77,78 through histopathologic evidence,^{48,50,53,54,59,61–63,71,72,76–80} and edema or congestion^{41,54,67,68,71–74,76,78,92} are included in Supplemental Digital Content, Table S3 (http://links.lww.com/JOM/C382). In histopathology reports, inflammatory infiltrates were typically noted in the lower respiratory tract and/or the nasal turbinates.⁷² Within lung tissue, infiltrating leukocytes were either broadly distributed or concentrated into foci (granulomas) or “cuffs” around the vasculature^50,54,72 and comprised macrophages,⁷¹ neutrophils,^79,80 and/or lymphocytes.^48,71,79

These histologic observations were consistent with increased leukocytes in BALF from six out of seven studies in rats and mice. BALF leukocyte elevations were usually driven by increases in granulocytes, particularly neutrophils^{71,72,77,78,91}; however, decreases in total cell counts were also reported, especially after longer exposure durations.^{71,74,77,78,93}

In vitro experiments from various groups provided further mechanistic evidence that jet fuel exposure may cause inflammation through the release of proinflammatory mediators (Supplemental Digital Content, Table S2, http://links.lww.com/JOM/C381). JP-8 exposure in cultured rat alveolar type II cells (RLE-6TN) or Fischer 344 (F-344) rat primary alveolar macrophages prompted the release of proinflammatory chemokines.^{62,87,88,94,95} JP-8 exposure was also associated with the prolonged activation of PARP-1, a coactivator of nuclear factor kappa beta (NF-κB), which controls the expression of many proinflammatory genes.^87,88

Findings suggest that jet fuel exposure induces time-dependent changes in inflammation (Fig. 5). In three studies of rats exposed to JP-8 for 7,^71,76,82 28,^71,76,82 or 56 days,^71,76 pulmonary inflammation and hemorrhage were described as “widespread” after 7 days of exposure, but diminished over time, with longer exposures showing only minor or localized effects. These patterns were paralleled by initial increases in BALF inflammatory cells after 7 days of exposure, returning to normal after 28 days, followed by reductions in leukocytes counts after 56 days.⁷¹ This study was the only one identified that quantified immune cell populations in BALF with an exposure paradigm greater than 14 days, highlighting a critical data gap.

In addition to these studies, the type and severity of histopathologic responses across reports were consistent with the pattern above. Respiratory inflammation was frequently noted as being more severe following short-term exposure.^{71,74,78,82,93} Conversely, subchronic exposure inflammatory processes were typically described as “minimal,” “mild,” or “scattered,“^{53,59–61,71,79} with chronic exposure studies infrequently reporting inflammation as an outcome.⁵⁴ Whether inflammatory effects resolve following a nonexposure recovery period could not be clearly established based on the available data. Two studies noted that mice and rats exposed to jet fuel for 1 year, followed by a 1-year recovery period, exhibited increased hyalin degeneration crystals,^50,54 whereas another subchronic exposure study reported increased incidences of nasal hyaline degeneration.⁵³ This common background lesion consists of proteinaceous material that accumulates in the cells of the respiratory epithelium and is noted to increase with age and chronic toxic exposures.^96,97 Although poorly characterized, this change is thought to represent an adaptive response to chronic insult.⁹⁷

Airway Remodeling and Lung Weight

Evidence of airway remodeling was observed in animal studies and supported by mechanistic evidence. Airway remodeling is a pathogenic process in which the size, mass, or number of airway tissues changes in response to repeated injury or chronic inflammation.^98,99 This process is characterized by increased thickness of airway walls, fibrosis, mucus hypersecretion, expansion of pulmonary vasculature, enlargement of smooth bronchial muscles, and ineffectual tissue repair.⁹⁹

Histopathological effects consistent with airway remodeling (Supplemental Digital Content, Table S4, http://links.lww.com/JOM/C383) first appeared in mice after 7 days of exposure to JP-8, with the reported thickening of alveolar/airway epithelium.^71,76 This was commonly observed across exposure designs and jet fuel types. Another ubiquitous effect was the hyperplasia or metaplasia of secretory cells, including the proliferation of type II airway epithelial cells^{71–73,75,81} in the lung and goblet cells^{49,50,59,62,63,79,80,100} in the upper respiratory tract. Fibrosis was observed in rats after 5 or 10 days of exposure to hydroprocessed esters and fatty acids-F (HEFA-F)⁶² or after 56 days of exposure to JP-8.⁷¹ After 90 days of exposure to JP-8, the alveolar capillaries of male rats became enlarged and distended.⁹² Damage to the alveolar structure was also observed in mice following exposure to jet fuels^72,73,78 (Supplemental Digital Content, Table S1, http://links.lww.com/JOM/C380).

Several mechanistic studies reported evidence that jet fuel exposure may promote airway remodeling (Supplemental Digital Content, Table S2, http://links.lww.com/JOM/C381). These include aspects of the inflammatory response and the differential expression of genes in pathways related to cell growth, cell surface changes, extracellular matrix, cytoskeleton, and cell signaling. For example, rats exposed to JP-8 for 7 days exhibited early signs of pulmonary fibrosis and the overexpression of myosin heavy-chain polypeptide 7 (Myh7), which plays a role in the extracellular matrix and cytoskeleton remodeling and is associated with chronic lung hyperinflation in humans, and γ-synuclein (Sncg), which is implicated in the regulation of vesicular trafficking, cell growth, and signaling transduction.³⁹ Another study in male mice exposed to JP-8 for 7 days observed decreased expression of alpha1–anti-trypsin (AAT).¹⁰¹ This protein protects connective tissues by inactivating elastase and trypsin, thereby counteracting the effects of degradative enzymes released by inflammatory cells. AAT deficiency can lead to uncontrolled destruction of alveolar epithelial connective tissues and reduced lung elasticity, which can impair lung function and is a primary risk factor for COPD and emphysema.¹⁰² Rat alveolar macrophages⁸⁷ and/or airway epithelial cells⁸⁸ exposed to JP-8 also had increased expression of NF-κB, IL-1α, and IL-1β, proinflammatory mediators that also promote airway remodeling.^{87,88,103–105}

Overall, the types of airway remodeling changes observed varied with exposure duration (Fig. 5). Evidence of airway remodeling was observed after 7 days, with thickening of the airway epithelium^71,73,76 and proliferation of type II pneumocytes.^71,81 This effect was observed throughout differing exposure durations and jet fuel types. Fibrosis was visible after 5 to 10 days⁶² or 56 days of exposure to JP-8.⁷¹ Pulmonary vascular remodeling was apparent after 90 days of exposure.⁹² In addition, goblet cell hyperplasia was commonly observed in the upper respiratory tract of subchronically and chronically exposed animals.^{50,59,61,63,79}

Tissue damage, inflammation, and airway remodeling can alter the structure and composition of the lungs. An approach to assess the cumulative effect of these changes is to examine lung weight. Five of five studies observed that lung weight changed following exposure to a variety of jet fuels regardless of exposure design and species (Supplemental Digital Content, Table S4, http://links.lww.com/JOM/C383). Four of five studies reported increased lung weight following short-term, subchronic, or chronic exposure to JP-8,⁸² S-8,⁷⁹ S-8 with JP-8 additive,⁸⁰ and JP-4¹⁰⁰ in rats. One short-term study noted decreased lung weight in rats exposed to JP-4.⁵⁶ Taken together, these findings suggest that jet fuel inhalation can initiate airway remodeling changes through various molecular mechanisms and can alter lung weight.

Lung Function

Lung function was assessed in both animal and human studies (Supplemental Digital Content, Table S5, http://links.lww.com/JOM/C384, and Supplemental Digital Content, Table S6, http://links.lww.com/JOM/C378). Two epidemiologic, cross-sectional studies examined lung function via spirometry measurements in airport workers occupationally exposed to jet fuels, and neither observed significant changes.^106,107 These included a study of Danish Air Force ground crews¹⁰⁶ and a study comparing exposure groups working at Birmingham International Airport.¹⁰⁷

Of the 13 animal studies^{52,62,69,70,72–75,77,78,82,108,109} assessing lung function changes, 10 noted adverse effects^{52,62,69,70,75,77,78,82,108,109} (Supplemental Digital Content, Table S5, http://links.lww.com/JOM/C384). Three studies demonstrated that for a wide variety of jet fuels, 30 minutes of exposure reduced respiration rates in rats and mice.^62,108,109 Moreover, multiple studies in rodents observed that jet fuel exposure altered measures of compliance and/or pulmonary resistance.^{52,69,70,77,82} These effects align with other tissue-level jet fuel exposure effects (eg, neurogenic inflammation, tissue damage, airway remodeling, inflammation, etc) and are further discussed in the Discussion section.

The duration of exposure effects was not examined in epidemiologic studies. Most lung function assessments in animal studies were conducted in exposures lasting 14 days or less (Fig. 5). Two studies from the same research group noted that reduced respiration rates in mice following 30 minutes of exposure to nine different jet fuels persisted after a short, 10-minute, postexposure recovery.^108,109 These results suggest that exposure to several types of jet fuels may impact lung function beyond the initial exposure period.

Respiratory Symptoms and Disease

As respiratory symptoms and disease endpoints were not measured in animals and cannot be measured in mechanistic systems, only epidemiologic studies were evaluated. The most frequently examined outcomes were self-reported respiratory symptoms (Supplemental Digital Content, Table S7, http://links.lww.com/JOM/C379). Five of nine studies observed an increase in symptoms in exposed populations,^{107,110–113} although the types of symptoms that were examined varied by study. A cross-sectional study of workers at Birmingham International Airport observed significantly increased cough with phlegm and runny nose in men in the high- versus medium-exposure groups.¹⁰⁷ Increased respiratory symptoms were also reported in a study of Hill Air Force Base personnel, who had a higher frequency of nose and throat irritation, cough, and shortness of breath compared to unexposed individuals, although statistical comparisons were not conducted.¹¹⁰ Symptom prevalence varied after the base transitioned from JP-4 to JP-8, with symptoms initially decreasing at 6 months and then increasing after 18 months.

In studies of exposed factory workers, findings were mixed. One study reported increased symptoms of “pain upon inhalation,” “slight cough,” and “feelings of suffocation,” in a small cohort study of Swedish workers,¹¹¹ whereas another reported no differences in a cross-sectional study of Swedish motor factory workers.¹¹⁴ Adverse respiratory symptoms were also reported following the release of JP-5 into the water distribution system at Joint Base Pearl Harbor-Hickam (JBPHH) in November 2021; the affected well was shut down after 9 days, the tanks defueled, and affected families were relocated in December 2021.¹¹⁵ Although statistical analyses were not conducted, the most commonly reported symptoms included a burning sensation in the nose or throat, runny nose, coughing, difficulty breathing, a burning sensation in the lungs, and nose bleeds. For some individuals experiencing adverse effects, symptoms persisted for 30 days or more. A records-based event analysis following this contamination event similarly found that increases in weekly medical visits for respiratory symptoms, such as cough, rhinorrhea, shortness of breath, and respiratory conditions, were reported by impacted individuals throughout a 1-year observation period.¹¹³ Additionally, increases in mucosal membrane–related visits, which included respiratory (eg, throat pain and chest pain with breathing) and nervous system (eg, ocular pain, eye lacrimation, and chemical conjunctivitis) outcomes, were noted.¹¹³ Although the symptoms reported in epidemiologic studies may be indicative of adverse effects, they were highly nonspecific and did not provide insight into the severity of effects or underlying mechanisms. However, significantly increased chronic cough was reported in male workers at an airport in Taiwan who were exposed to unspecified jet fuels.¹¹² Chronic cough can be associated with chronic inflammation and may be characteristic of COPD, especially chronic bronchitis. Wheezing was noted in adults and children following the JBPHH JP-5 contamination incident, although the prevalence of this symptom was low (adults: 9%, children: 6%).¹¹⁵ The study of workers at Birmingham International Airport observed no differences in self-reported wheezing or whistling in the chest in the past 12 months.¹⁰⁷

Two epidemiologic studies examined associations between jet fuel exposure and respiratory diseases,^112,116 with mixed findings. In a cohort study of former civilian workers at Hill Air Force Base, Utah, a significant increase in nonmalignant respiratory disease mortality was observed in male workers exposed to JP-4 compared to unexposed male workers.¹¹⁶ In addition, a cross-sectional study of airport workers in Taiwan reported a nonsignificant increase in chronic bronchitis when comparing exposed and unexposed workers.¹¹² One study compared rates of mortality due to any respiratory disease in a cohort of Swedish Armed Forces personnel to the Swedish general population using standardized mortality ratios (SMRs) and observed no increase in cases of respiratory mortality.¹¹⁷ Most epidemiologic studies examined acute health effects following low-level chronic exposures; however, two case reports discussed the effects following high-level acute accidental exposures. This included pneumonitis,¹¹⁸ respiratory arrest, dyspnea, and widespread crepitations in the lung.¹¹⁹

DISCUSSION

Jet fuel exposure is a significant health concern for active-duty service members and veterans. Here, we reviewed evidence from human, animal, and mechanistic studies to assess the effects of jet fuel exposure on the respiratory system. Overall, the available data suggested that jet fuel inhalation results in tissue damage, inflammation, and airway remodeling, which could ultimately lead to changes in lung function and respiratory symptoms or disease. Although knowledge gaps remain, drawing from supporting literature provides a more cohesive explanation for how these adverse effects occur and what health outcomes are most likely.

Although there is evidence suggesting that jet fuel inhalation causes respiratory tissue damage and cytotoxicity, the molecular mechanisms driving these effects have not been fully characterized. Research on similar chemicals has shown that highly hydrophobic constituents, including cyclic hydrocarbons, specifically terpenes, aromatics, or cycloalkanes, can be directly cytotoxic by damaging cell membranes or altering cell permeability.¹²⁰ Reactive jet fuel components, such as benzene, naphthalene, or paraffins, can also damage airway tissues by metabolizing into bioactive intermediates through interactions with proteins or transcription factors, such as the aryl hydrocarbon receptor (AhR).^27,121–123 AhR is a ligand-activated transcription factor that can be activated by cyclic hydrocarbons, thus triggering the upregulation of xenobiotic-metabolizing enzymes, including cytochrome P450 monooxygenase 1A1 (CYP1A1). These enzymes can metabolize hydrocarbons and form reactive oxygen species (ROS), which can then form deoxyribonucleic acid (DNA) adducts or bind to other molecules.¹²⁴ Although this mechanism is known to be important in explaining the toxicity of individual jet fuel subcomponents, some studies suggest that its role in jet fuel exposure–related effects may be less important.^37,125

Jet fuel–induced tissue damage and cytotoxicity also provide a likely mechanistic explanation for the release of proinflammatory mediators following jet fuel exposure. Components from damaged or lysed cells are recognized as damage-associated molecular patterns (DAMPs) by neighboring immune and epithelial cells, prompting the release of cytokines, chemokines, and other proinflammatory mediators. The increased presence of intracellular components (eg, LDH, NAG) in BALF^72–74,91 supports a similar paradigm whereby jet fuel–induced damage promotes the release of intracellular DAMPs, leading to a proinflammatory response (Supplemental Digital Content, Table S2, http://links.lww.com/JOM/C381). These mediators can promote inflammation in the lung and alveolar space in response to stress stimuli by recruiting neutrophils, monocytes, and macrophages; stimulating T cells or B cells; or activating phagocytes to ingest foreign material and remove dead cells.^88,126,127 The infiltration of immune cells and recruitment of neutrophils by proinflammatory cytokines can cause granular enzyme release and the formation of neutrophil extracellular traps. This results in ROS formation and additional tissue damage, creating a positive feedback loop enhancing the inflammatory response, alveolar damage, and pulmonary edema.¹⁷

Additional questions also remain regarding the apparent reduction in the inflammatory response that occurs during subchronic or chronic inhalational jet fuel exposures.^71,82 Possible explanations may include immunotoxicity, immune modulation via adaptation or tolerance, or a combination of these effects. To balance the role between help and harm, the respiratory system can “adapt” or acquire “tolerance” to proinflammatory challenges in which inflammatory responses are reduced despite repeated, continued exposure. This phenomenon has been long observed in other repeated inhalational exposures, notably for the air pollutant ozone and lipopolysaccharide (LPS), a highly proinflammatory component of bacterial cell walls.^128–132 A variety of underlying adaptive mechanisms have been identified, that include both physiological changes in the airway and molecular changes in epithelial and immune cells.^{129,130,133,134} In addition, reduced inflammatory response may also be explained by direct inhibitory or cytotoxic effects on immune cells.¹³⁵ More studies are required to understand the effects of prolonged jet fuel exposure on the respiratory inflammatory response. Bridging this data gap is important because toxicity studies could potentially be biased toward the null by missing a critical window of susceptibility when inflammation and tissue damage are most severe.

Jet fuel inhalation altered various lung function parameters in animal studies that may inform potential health effects in humans. For example, a decreased respiration rate in rodents following inhalational jet fuel exposure is an indication of trigeminal nerve sensory irritation in the upper respiratory tract (typically an acute effect that could dissipate once exposure to the irritant is removed), which in humans could correspond to neurogenic inflammation and a burning or painful sensation.^136,137 Previous research has established how altered respiratory rates, including lung compliance, can be indicative of altered lung function, as has been demonstrated in the context of COPD, emphysema, or sarcoidosis.^138,139 To detail, increased compliance measures may indicate expanded lung volume that could be explained by the loss of tissue via overt tissue damage and the loss of lung elasticity, as often occurs in emphysema.¹³⁸ Increases in inspiratory resistance could be explained by the physical blocking of airways (ie, reduced airway caliber) by debris, mucus, swelling, or by airway remodeling–associated changes that stiffen or obstruct the airway, such as fibrosis, airway thickening, or vascular remodeling, as often occurs in COPD and asthma.^140,141 The relative contribution of processes increasing pulmonary compliance and/or resistance likely depends on various factors (eg, animal model, exposure concentration, exposure duration, jet fuel type) and represents an important area for future research.

Many of the aforementioned effects involving tissue damage, inflammation, and airway remodeling occur in individuals who are occupationally exposed to lung irritants and result in respiratory disease.^142,143 As such, individuals who are occupationally exposed to jet fuels, such as service members and veterans, may be at risk of developing or exacerbating preexisting respiratory diseases. Of particular concern is COPD, especially emphysema and chronic bronchitis. Emphysema can develop following repeated tissue damage and is characterized by the disruption of alveolar architecture and/or the overinflation of the lungs due to loss of connective tissue and lung elasticity. Chronic bronchitis can arise from chronic inflammation in the bronchi and is characterized by thickened airways and increased mucus production caused by the hyperproliferation of mucus-secreting cells.

In addition, increased airway responsiveness, hypersensitivity, and the development or exacerbation of asthma can occur with the repeated inhalation of irritants. Jet fuel–associated changes in the airway that may mediate these effects include the increased presence of inflammatory cells in the airway (especially eosinophils and basophils), vascular remodeling, and enhanced leakiness of the airway.¹⁴⁴ These airway diseases can be associated with reductions in lung function and symptoms, such as shortness of breath, difficulty breathing, wheezing, coughing, increased phlegm production, and increased susceptibility to infection.

Epidemiologic Data Summary and Synthesis

There was slight epidemiologic evidence that jet fuel exposure negatively impacts respiratory health, including adverse respiratory health outcomes, such as long-term respiratory disease mortality and short-term and long-term respiratory symptoms (Table 1 and Supplemental Digital Content, Table S8, http://links.lww.com/JOM/C326). Despite the strength of the animal and mechanistic data, the epidemiologic evidence that aligns with these findings is based on low confidence and uninformative studies. In low confidence studies, observations like significantly increased nonmalignant respiratory disease mortality in exposed Air Force base workers and significantly increased respiratory symptoms, including dyspnea and chronic cough, in exposed airport workers were coherent with findings of increased cellular inflammation and respiratory tissue damage. Similarly, several uninformative studies, case reports, and secondary data sources presented supplemental evidence (both significant and nonsignificant) of respiratory effects (eg, pneumonitis, respiratory hypersensitivity, increased frequency of short-term and long-term respiratory symptoms) following jet fuel exposures. These symptoms align with potential health effects that could be associated with changes in immune cell populations and chronic inflammation, as demonstrated by the animal evidence. Overall, Although findings from the available epidemiologic studies are consistent with the animal and mechanistic data, the low quality of these studies clearly demonstrates the need for more well-designed epidemiologic studies.

TABLE 1.

Summary of the Epidemiologic and Animal Toxicological Evidence Synthesis, and Evidence Integration Strength of Evidence Judgment Calls

Evidence Stream	Strength of Evidence Judgment	Description
Epidemiologic	Slight	Studies reported a link between jet fuel exposure and respiratory health outcomes with considerable uncertainty; evidence was limited to one medium confidence study and multiple low confidence and uninformative studies.
Animal toxicological	Moderate	Primarily consistent evidence of an association between jet fuel exposure and adverse respiratory outcomes supported by at least one high and medium confidence study that did not reach the degree of certainty required for a robust rating.
Epidemiologic, animal toxicological, and mechanistic	Evidence indicates (likely)	The evidence base indicates that jet fuel exposure likely causes respiratory health outcomes in humans, although there are outstanding questions or limitations that remain, and the evidence was insufficient for a higher conclusion level.

Animal Toxicological and Mechanistic Data Summary and Synthesis

There is moderate animal toxicological evidence that jet fuel exposure results in lung toxicity (Table 1 and Supplemental Digital Content, Table S8, http://links.lww.com/JOM/C326). All 10 studies evaluating ultrastructural changes reported evidence of damage while histopathological analyses identified tissue alterations in 19 of 28 studies. When results were compared by study confidence level, no clear patterns emerged, as both high and medium confidence studies reported a mix of positive and null findings. Of the inhalation studies that reported the average mass median aerodynamic diameter following exposure to an aerosol vapor mixture, the particle size was reported to be below 4 μM. It has been reported by the OECD¹⁴⁵ that aerosols with particle size distributions between 1 and 4 μM are generally considered respirable by rodents, suggesting that histopathological differences may be due other exposure paradigm differences (eg, fuel type, exposure length, animal model) rather than particle size. Notably, studies evaluating oral gavage or dermal exposures (n = 4) did not identify histopathological changes, which may reflect reduced direct lung exposure. Although histopathological findings were somewhat variable, tissue injury was generally dose-dependent and observed in both the upper and lower respiratory tract. Mechanistic evidence supports these observations, indicating that cytotoxicity is mediated by cellular stress pathways and loss of membrane integrity. Limited time-course evaluations in low and medium confidence studies suggest that tissue injury can persist for a period of at least 4 weeks in rats, although these outcomes subsided by week 14.

Pulmonary inflammation was a recurrent outcome across animal studies. Fifteen of the 19 inhalation studies documented increased inflammatory markers following exposure, and histological observations were consistent with enhanced immune cell infiltration. Six of the seven bronchoalveolar lavage fluid (BALF) studies in rats and mice demonstrated increased leukocyte populations, including macrophages and eosinophiles. Mechanistic data corroborated these findings, suggesting that exposure to jet fuel stimulates the release of proinflammatory mediators that drive cellular recruitment and inflammatory signaling. At the tissue level, 15 of 18 inhalation studies reported changes in pulmonary architecture, immune cell localization, or vascular alterations consistent with chronic inflammatory processes.

Beyond acute injury and inflammation, repeated exposures were associated with airway remodeling and impaired respiratory function. Epithelial thickening was commonly reported across exposure designs and jet fuel types. Hyperplastic or metaplastic changes in secretory cells were observed in both the upper and lower respiratory tract including proliferation of type II epithelial cells in the lung and goblet cells in the nasal passages. Organ-level indicators, such as increased lung weight in four of five studies, were coherent with inflammation and permeability changes. Ten of 13 studies that evaluated lung function reported adverse outcomes, including reduced respiratory rate, altered pulmonary compliance, and increased airway resistance. Together, these data support a consistent pattern in which jet fuel exposure leads to cytotoxic injury, sustained inflammation, and airway remodeling, leading to impaired lung function.

Evidence Integration

Considering the available evidence from epidemiologic, animal toxicological, and mechanistic studies, evidence indicates that exposure to jet fuels is likely to cause respiratory toxicity in humans under relevant exposure circumstances (Table 1 and Supplemental Digital Content, Table S8, http://links.lww.com/JOM/C326). This conclusion is based primarily on consistent evidence of alterations in pulmonary inflammation, lung permeability, histopathologic evidence of airway remodeling, and lung weight changes in animal toxicological studies, as well as supporting evidence of an association in epidemiologic studies. In animal models, the consistency of effects and the concordance across cell-organ–tissue level observations suggest that effects observed in humans may be related to chronic obstructive lung disorders and increased susceptibility to respiratory infections. The available mechanistic information supports these phenotypic effects by demonstrating concordant activation of relevant molecular and cellular pathways across human and animal models.

Although uncertainty remains given the limited number and quality of epidemiologic studies, findings of increased respiratory symptoms and nonmalignant respiratory disease mortality in exposed worker populations are broadly aligned with animal evidence for inflammation, tissue injury, and airway remodeling. Supplemental evidence from case reports and secondary data sources also point toward respiratory hypersensitivity, pneumonitis, and chronic symptoms consistent with chronic inflammatory processes observed in animals. Importantly, when comparing results by study confidence level, no clear patterns emerged. High, medium, and low confidence studies reported both positive and null findings.

Taken together, the evidence streams are coherent and biologically plausible. Animal and mechanistic data provide strong evidence that jet fuel exposure induces cellular injury, inflammation, and structural remodeling of the respiratory tract, and the limited but supportive epidemiological evidence suggests that similar outcomes may occur in human populations. While the animal findings suggest structural remodeling and inflammatory patterns that resemble obstructive lung disease, the human data are too limited and inconsistent to draw firm conclusions about this disease linkage. Future population-based studies should focus on improving exposure characteristics in exposed cohorts, applying consistent diagnostic criteria for obstructive lung disease, and using longitudinal designs to better capture early respiratory effects and long-term disease outcomes. Although uncertainty remains, particularly regarding long-term respiratory outcomes, the integration of these evidence streams indicates a likely hazard of respiratory toxicity from jet fuel exposure. Additional epidemiologic studies of prospective design with adequate follow-up are needed to assess health outcomes consistent with those identified in the available animal toxicological data.

Data Gaps and Limitations

This review identified key gaps and limitations in the epidemiologic and animal toxicological evidence base. For epidemiologic studies, no high confidence studies were available, and only one medium confidence study reported on pulmonary function in exposed individuals. Lack of statistical comparisons, potential selection bias, and insensitive measurement methods were significant causes of downgraded study quality. Most epidemiologic studies examined respiratory health outcomes following civilian occupational exposure to jet fuels, although several case reports and secondary sources described adverse respiratory effects in military personnel following jet fuel exposure events. This, in combination with the limited quantity of resources, restricted the ability to draw conclusions about health outcomes in military populations. To strengthen the epidemiologic evidence base, more high-quality studies that measure long-term health outcomes after exposure has ended, especially for chronic airway diseases, are required. In addition, prospective cohort studies that feature reliable exposure assessment and sufficient follow-up time to collect data on health outcomes with long latency periods or those that tend to develop later in life are warranted.

Animal studies provided moderate evidence of jet fuel toxicity; however, generalizability to human exposure effects was complicated by several limitations. First, most studies featured exposure and/or exposure regimens that were often much higher or more intensive than realistic human exposure scenarios, making it difficult to anticipate the likelihood or severity of exposure effects. Second, endpoints that might be more relevant to predicting respiratory health outcomes in chronically exposed service members, such as lung function assessments, were not performed on chronically or even subchronically exposed animals. Despite these limitations, this review was strengthened by the use of a systematic approach tailored to the VA's needs to understand the long-term health implications of jet fuel exposure and the robust analysis of three evidence streams (ie, epidemiologic, animal toxicological, and mechanistic) to drive conclusions.

Although objective data on jet fuel exposure during military service are scant, self-reported exposure data may yield important insights and suggest promising areas of future research. For example, the Service and Health Among Deployed Veterans study collected a detailed exposure history among 1920 veterans deployed to Afghanistan and Southwest Asia after 2001 and found that refueling or maintenance operations were the military occupations with the longest duration of exposure (median, 5.0–6.53 months) to vapors, gases, dusts, or fumes.¹⁴⁶ This finding would seem to support the broader trends observed in the National Airborne Hazards and Open Burn Pit Registry (AHOBPR). Among 496,838 AHOBPR participants, more than half endorsed exposure to refueling operations and engine maintenance while deployed. In a typical month of deployment, those activities occurred on 17.0 and 19.9 days, respectively (N. Jani, personal communication, January 22, 2025). Lastly, unpublished clinical operations data from 546 veterans referred for specialty cardiopulmonary clinical evaluation at the VA's War Related Illness and Injury Study Center (New Jersey) have also been examined. With respect to “petrochemical fuels or fumes,” 91% endorsed exposure during their deployments, with 62% stating they were exposed every day during deployment (G. Pappas, personal communication, January 22, 2025). Taken together, probable exposure to jet fuels appears commonplace when assessed via structured interview in a research setting by participants of a volunteer registry,¹⁴⁶ or endorsed as part of a specialty clinical evaluation (G. Pappas, personal communication, January 22, 2025). Notably, jet fuel exposure does not occur in isolation during military service, but rather in concert with a myriad of other potential military environmental exposures (eg, dust, sand, burn pit smoke). For these reasons, it is difficult to associate a specific exposure with a respiratory health outcome. Still, there is suggestive evidence, such as an increasing prevalence of interstitial lung disease among previously deployed veterans¹² that is consistent with preclinical findings that indicate the presence of fibrosis secondary to jet fuel exposure.^39,62 Importantly, these conditions in humans are slow to develop and unlikely to be detected shortly after exposure. Moreover, overreliance on lung function screening tests, such as spirometry, may overlook the effects of jet fuel exposure that could manifest in more subtle findings. Alternative modalities, such as respiratory oscillometry, lung clearance index, and imaging-based modalities, may afford greater sensitivity in evaluating the chronic effects of jet fuel exposure in this population.^147–149 Future investigations seeking to understand the potential impact of jet fuel exposure on pulmonary function should consider novel assessments in addition to standard screening tests (spirometry).

Future research in animal models should focus on long-term exposure outcomes, the persistence of effects, and highly relevant endpoints, such as lung function and susceptibility to respiratory infections. Moreover, additional studies identifying the mechanisms underlying adverse effects may help identify interventions or ways to ameliorate exposure effects. Additional research in veterans or other exposed human populations should assess pulmonary function and chronic airway disease to confirm putative health effects suggested by animal models. Furthermore, studies in exposed human populations will provide additional knowledge and context to inform clinicians about jet fuel–related respiratory disease risks and progression.

In conclusion, this systematic review synthesized epidemiologic, animal toxicological, and mechanistic evidence and concluded that jet fuel exposure likely causes adverse respiratory health outcomes in humans. This conclusion was based on moderate evidence of adverse effects in inhalational animal exposure studies and concordance with relevant mechanistic data and was slightly supported by epidemiologic evidence. Pivotal data gaps and future research opportunities that will be critical to protecting the health of exposed service members were identified.