Understanding the Neurologic and Cognitive and Behavioral Effects Associated With Exposures to Jet Fuels

Overall, results from human and animal studies suggest that exposure to jet fuels may cause neurotoxicity in humans. This increased understanding of short- and long-term neurologic, cognitive, and behavioral effects can assist in guiding clinical care.

Abstract

Objective

This study aimed to assess the neurologic, cognitive, and behavioral effects of jet fuels used by the US military.

Methods

A fit-for-purpose systematic literature review approach based on the US EPA's IRIS handbook was used to conduct a comprehensive assessment of the scientific evidence. Data were synthesized to evaluate evidence for specific neurologic health outcomes.

Results

Short- and long-term adverse effects on sensory functions (ie, auditory, visual), memory and cognition, motor coordination, and peripheral nervous system were observed in human and animal studies following exposure to jet fuels.

Conclusions

The evidence indicates that exposure to jet fuels is likely to cause neurotoxicity in humans. Overall, the results indicate that the nervous system is sensitive to jet fuel exposure; however, uncertainty remains due to the limited number of quality epidemiologic studies and the large variety of jet fuels studied.

LEARNING OUTCOMES

• Upon reviewing this manuscript, readers will be able to:

• Demonstrate the ability to synthesize the possible neurologic, cognitive, and behavioral health effects associated with exposure to jet fuels based on the available epidemiologic, animal toxicological, and mechanistic evidence.

• Define the key data gaps and outline future research opportunities to increase the ability to make causal determinations regarding neurologic, cognitive, and behavioral health effects associated with jet fuel exposure, based on findings of this review.

The United States (US) military and National Guard employed over two million men and women in both active and reserve roles in 2022.¹ Despite the stringent health and fitness standards required to join and remain in service, US veterans experience higher morbidity rates compared to nonveterans, according to data collected from 2003 to 2019. Service members experience various physical and mental stressors during service that can adversely impact health long-term (eg, extreme temperatures² and combat trauma³). In addition to the dangers of military service related to deployments and/or combat, service members also encounter numerous toxic substances during their careers, which may lead to worse health outcomes.^3–6 For example, military personnel are exposed to occupational hazards such as loud noise,⁷ psychological stress,⁸ environmental contaminants (eg, PFAS-contaminated drinking water⁹), or other chemicals related to lifestyle factors (eg, smoking¹⁰). These factors can heighten susceptibility to adverse health effects or amplify the impacts of military environmental exposures.

Exposure to jet fuel is a common occupational and environmental hazard for military personnel.¹¹ Those involved in aircraft fueling, defueling, maintenance, performance testing, and the storage or transportation of jet fuel face increased risks of exposure through inhalation, ingestion, and dermal contact.^12–15 Because of their widespread use in military operations, veterans commonly express concerns about how exposures to jet fuels may impact their long-term health. As a result of these concerns, the US Department of Veterans Affairs (VA) was directed to investigate the potential links between jet fuel exposure and adverse health outcomes. A recent systematic review conducted by the VA assessed the available occupational epidemiologic literature related to jet fuel exposure.¹⁶ The review noted several studies that reported neurologic outcomes focused on the short-term effects of jet fuel exposure, such as headache, dizziness, and fatigue; sensory function (including impacts on auditory processing and noise-induced hearing loss); eye irritation; and cognition, including attention and executive function; however, data detailing the long-term neurotoxic effects of exposure to jet fuels or kerosene (the primary constituent of most jet fuels) remain scarce. Similarly, previous reviews and analyses by authoritative bodies, such as the Agency for Toxic Substances and Disease Registry (ATSDR),¹¹ the National Research Council (NRC),¹⁷ and the National Academies of Sciences, Engineering, and Medicine,¹⁸ have reported limited data characterizing long-term neurologic effects in humans following exposure.

These data gaps underscore the need for further research to better understand both short- and long-term impacts of jet fuel exposure. This systematic literature review expands upon VA's previous review¹⁶ by comprehensively integrating data from multiple evidence streams (ie, epidemiologic, animal toxicological, and mechanistic data) to identify adverse neurologic, as well as cognitive and behavioral health effects following jet fuel exposure.

METHODS

This work builds on an earlier review of the occupational literature.^16,19 This systematic review of the epidemiologic, animal toxicological, and mechanistic literature on the health effects of occupational jet fuel exposure was carried out following the US Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) assessment framework, detailed in the IRIS Handbook.^20,21 The IRIS methodology, which considers the whole body of scientific literature by considering epidemiologic studies, animal toxicological studies, and mechanistic evidence, was used because it is an established framework that is used for the identification and characterization of health hazards due to chemical exposures to support decision-making in science. In addition, the current work sought to examine the effect of length of exposure duration to jet fuels on health outcomes and the link between immediate symptoms and long-term health outcomes.¹⁹ The following is a brief summary of the methods utilized to identify, evaluate, and synthesize the available evidence related to the association between jet fuel exposure and effects on neurologic and cognitive behavioral health in humans. A more comprehensive description of these methods is detailed in Bergeron et al.²²

Literature Search Strategy

The detailed search approach to identify relevant epidemiologic, animal toxicological, and mechanistic studies was developed under the guidance of the Population, Exposure, Comparator, and Outcomes (PECO) criteria.²² Literature searches identified relevant epidemiologic, animal toxicological, and mechanistic studies through March 2025. To ensure a comprehensive review of the body of literature, the literature searches were conducted in four types of bibliographic sources: (1) scientific literature databases (PubMed and EBSCOhost); (2) gray literature, such as government reports not indexed in traditional scientific literature databases; (3) expert-identified publications and reports; and (4) references cited in identified epidemiologic and animal toxicological secondary reviews.

Inclusion and Exclusion Criteria

The PECO criteria guided the identification of the evidence that addresses the specific aims of the review and the literature search and screening processes, including study inclusion and exclusion.²² The relevant population included any human population (eg, military, occupational, general population) and life stage not limited by country; for animal toxicological studies, any vertebrates of any life stage; and for mechanistic data, any human, vertebrate, ex vivo/in vitro samples, and in silico models. Exposures to any type of jet fuel via any exposure route for any duration were considered relevant. Regarding comparators, comparison or reference populations exposed to lower levels (or no exposure) or for shorter periods of time were considered relevant. Relevant outcomes included any neurologic, cognitive, or behavioral health effect observed in humans, relevant animal toxicological models, or any neurologically relevant cellular, biochemical, or molecular changes related to jet fuel exposure. Case studies, case series, and secondary data sources (eg, literature reviews) were included in this review as supplemental information and were discussed within the synthesis of the evidence but were not considered in the weight-of-evidence determinations.

Literature Screening and Data Extraction

The PECO relevancy of all studies was determined during title/abstract; relevant articles then underwent full-text screening. Two independent reviewers performed the screenings with conflict resolution completed by a subject matter expert in epidemiology or toxicology. Studies identified as not relevant during the screening process did not move forward to data extraction or study quality evaluation.

Publications that reported on the same epidemiologic or animal toxicological study population were identified as overlapping or partially overlapping datasets. An overlapping dataset included multiple references that reported on the same endpoints from a single epidemiologic or animal toxicological study. In contrast, a partially overlapping dataset included multiple references that reported on the same animals across multiple publications, but unique endpoints and/or outcomes were reported in each publication. Overlapping datasets were not considered independently in the evidence synthesis; however, partially overlapping datasets were, as they reported on different endpoints.

Data extraction was conducted by one reviewer and verified by a second senior reviewer, a deviation from EPA's IRIS Handbook,²¹ for all relevant primary epidemiologic, animal toxicological, and mechanistic studies. All health outcomes were extracted, regardless of statistical significance or quality of the study.¹⁹ Only qualitative information was extracted from mechanistic studies and supplemental information, such as case reports, case studies, case series, and secondary reviews.

Study Quality Evaluation

Study quality evaluation was conducted by two reviewers for all relevant primary epidemiologic and animal toxicological studies using the approach outlined in the IRIS Handbook.²¹ However, in a deviation from this approach, each study was evaluated by one reviewer and verified by a second with any disagreements discussed with the evaluation team or a subject matter expert.

For each study quality domain, the reviewers assigned a rating of good, adequate, deficient, not reported (an animal toxicological-specific rating that could carry the same functional interpretation as adequate or deficient), or critically deficient.²¹ Then, overall study confidence (ie, high, medium, low, or uninformative)²¹ was determined based on the strengths and limitations identified. Study quality ratings were determined for each endpoint so that, within a single study, multiple study confidence judgments were possible if they differed by outcome. The overall confidence rating reflects interpretations of the potential influence of biases and limitations on the results across all domains. Per the IRIS guidelines,²¹ mechanistic studies, supplemental information, such as case reports, case studies, case series, and secondary reviews, and overlapping references did not undergo study quality evaluation. The rationale for study quality ratings are available on Tableau on the study quality evaluation heatmap tab: https://public.tableau.com/app/profile/vha.home/viz/SupportingInformationforVHAJetFuelsReport_17002413903760/ReadMe?publish=yes.

Evidence Synthesis and Integration

Syntheses of the evidence for epidemiologic and animal toxicological health effects were based on high and medium confidence studies when possible. Results from low confidence studies (epidemiologic and animal toxicological) and uninformative studies (epidemiologic studies only, due to the small number of primary epidemiologic literature) were given less weight.

Strength-of-evidence judgments within each evidence stream were made using standard terminology (eg, robust, moderate, slight, indeterminate, compelling evidence of no effect) and criteria from the IRIS Handbook,²¹ which adapts Hill's causality criteria²³ to evaluate several factors, such as study quality, consistency across studies, dose-response relationships, strength of association, outcome directness, and coherence of findings.

Evidence integration combined epidemiologic and animal toxicological evidence by considering various factors, such as the human relevance of animal findings, cross-stream coherence, susceptible populations, biological plausibility, mode of action, and supplemental mechanistic evidence. Mechanistic evidence further supported biological plausibility. Weight-of-evidence judgments were made using standard terminology (ie, evidence demonstrates, evidence indicates (likely), evidence suggests, evidence inadequate, strong evidence supports no effect) as outlined in the IRIS Handbook.²¹

RESULTS

Literature Search and Study Selection

The results of the study identification process are provided in Figure 1. The literature search returned a total of 4291 references, and 621 were deemed relevant during title/abstract screening. Full-text screening yielded 279 references that met the inclusion criteria, including 42 epidemiologic references, 125 animal toxicological references, and 113 references containing mechanistic data. A total of 117 references focused on neurologic or cognitive and behavioral health outcomes, including 24 epidemiologic references, 46 animal toxicological references, and 9 mechanistic references. For the epidemiologic and animal toxicological studies, there were multiple references that reported on the same study as other references. After accounting for overlapping datasets, there were 19 unique epidemiologic and 37 unique animal toxicological studies identified.

FIGURE 1.

Reference flow diagram of the search, screening, and selection of neurologic and cognitive and behavioral 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, 117 specifically discussed neurologic and cognitive and behavioral health effects of jet fuel exposure, including 24 epidemiologic references, 8 case reports or case series, 46 animal toxicological references, 9 mechanistic references, and 30 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. ^dFive references reported on the same epidemiologic study of neurologic and cognitive and behavioral health. After excluding reports of the same data, there were 19 unique epidemiologic studies in this body of literature. ^eNine references reported on the same animal toxicological study of neurologic and cognitive and behavioral health outcomes. Five additional references were classified as a partial overlap, as they reported on a portion of the same neurological endpoints as another reference; however, all other neurological endpoints reported were unique. After excluding reports of the same data, there were 37 unique animal toxicological studies in this body of literature.

Data from all steps of the systematic review process were visualized using Tableau (Seattle, WA). The Tableau dashboard features a diagram following the Interactive REFerence Flow (I-REFF) approach to enhance the transparency and traceability of literature review results,²⁴ study quality evaluation heatmaps with detailed rationales for confidence scores for epidemiologic and animal toxicological studies, and evidence maps for all study types (epidemiologic, animal toxicological, and mechanistic). The dashboard is available at: https://public.tableau.com/app/profile/vha.home/viz/SupportingInformationforVHAJetFuelsReport_17002413903760/ReadMe?publish=yes.

Of the 19 primary epidemiologic studies that assessed neurologic or cognitive and behavioral health effects of jet fuel exposure, four were considered medium confidence, eight were low confidence, one was mixed confidence (low or uninformative depending on the outcome), and six were uninformative (Figs. 2 and 3). No epidemiologic studies were considered high confidence. Studies were considered low confidence or uninformative because of concerns for potential selection bias due to a lack of recruitment details, exposure misclassification due to measurement methods, outcome misclassification due to the use of self-reported symptoms, potential for residual confounding, or limited study sensitivity.

FIGURE 2.

Summary of study quality evaluation results for neurologic health outcomes for epidemiologic studies of jet fuel exposure. This heatmap provides an overview of the study quality ratings assigned to the 18 unique epidemiologic studies that reported neurologic effects following jet fuel exposure. The validity and utility of each study were assessed based on potential bias related to exposure measurement, outcome ascertainment, participant selection, potential confounding, analysis, sensitivity, and selective reporting. The evaluation domain rating (eg, good, adequate, deficient, critically deficient) and overall study confidence classification (eg, high, medium, low, uninformative) were determined by a primary and secondary reviewer for each study. Domain ratings and overall study confidence classifications were based on descriptions outlined in Section 4.1.1 of the IRIS Handbook²¹ and are further discussed in Bergeron et al.²² Of the 18 primary epidemiologic studies that assessed neurologic health effects of jet fuel exposure, 4 were considered medium confidence, 7 were low confidence, 1 was mixed confidence (low or uninformative depending on the outcome), and 6 were uninformative. ^aProctor et al²⁵ had an overlapping dataset with Heaton et al²⁶ for all neurological health outcomes; therefore, this article did not undergo study quality evaluation. ^bStruwe et al,²⁷ Knave et al,²⁸ and Mindus et al²⁹ had an overlapping dataset with Knave et al³⁰ for all neurological health outcomes; therefore, these articles did not undergo study quality evaluation. ^cMattie et al³¹ had an overlapping dataset with Mattie et al³² for all neurological health outcomes; therefore, this article did not undergo study quality evaluation.

FIGURE 3.

Summary of study quality evaluation results for cognitive and behavioral health outcomes for epidemiologic studies of jet fuel exposure. This heatmap provides an overview of the study quality ratings assigned to the seven unique epidemiologic studies that reported cognitive and behavioral outcomes following jet fuel exposure. The validity and utility of each study were assessed based on potential bias related to exposure measurement, outcome ascertainment, participant selection, potential confounding, analysis, sensitivity, and selective reporting. The evaluation domain rating (eg, good, adequate, deficient, critically deficient) and overall study confidence classification (eg, high, medium, low, uninformative) were determined by a primary and secondary reviewer for each study. Domain ratings and overall study confidence classifications were based on descriptions outlined in Section 4.1.1 of the IRIS Handbook²¹ and are further discussed in Bergeron et al.²² Of the seven unique studies that discussed cognitive and behavioral outcomes, one study was considered medium confidence, three were low confidence, and three were uninformative. ^aProctor et al²⁵ had an overlapping dataset with Heaton et al²⁶ for all neurological health outcomes; therefore, this article did not undergo study quality evaluation. ^bStruwe et al,²⁷ Knave et al,²⁸ and Mindus et al²⁹ had an overlapping dataset with Knave et al³⁰ for all neurological health outcomes; therefore, these articles did not undergo study quality evaluation.

Thirty-seven primary animal toxicological studies that examined the association between neurologic health outcomes and jet fuel exposure were identified. The study quality evaluation identified 3 high confidence, 4 mixed confidence (high/medium), 11 medium confidence, 2 mixed confidence (medium/low), 2 mixed confidence (medium/uninformative), 13 low confidence, and 2 uninformative studies (Fig. 4). Studies were identified as low confidence or uninformative for one or more of the following issues: lack of clarity regarding sources of reporting, incomplete information about animal allocation to exposure groups, concern for potential observational biases, contained confounding variables, high levels of attrition, lack of details on jet fuel characterization and administration, and/or lack of detailed results that reduced the ability to interpret findings. The two uninformative animal studies were not included in the synthesis of the evidence.^47,57

FIGURE 4.

Summary of study quality evaluation results for neurologic health outcomes for animal toxicological studies of jet fuel exposure. This heatmap provides an overview of the study quality ratings assigned to the 37 unique animal toxicological studies that reported neurologic health outcomes following jet fuel exposure. The validity and utility of each study were assessed based on potential bias related to exposure measurement, outcome ascertainment, participant selection, potential confounding, analysis, sensitivity, and selective reporting. The evaluation domain rating (eg, good, adequate, deficient, critically deficient) and overall study confidence classification (eg, high, medium, low, uninformative) were determined by a primary and secondary reviewer for each study. Domain ratings and overall study confidence classifications were based on descriptions outlined in Section 4.1.1 of the IRIS Handbook²¹ and are further discussed in Bergeron et al.²² Of the 37 unique studies that discussed neurologic outcomes, 3 studies were considered high confidence, 4 were mixed confidence (high/medium confidence), 11 were medium confidence, 2 were mixed confidence (medium/low confidence), 2 were mixed confidence (medium/uninformative), 13 were low confidence, and 2 were uninformative. ^aBogo et al³³ had a partially overlapping datasets with Parker et al³⁴ for some neurological health outcomes; this article underwent study quality evaluation for unique neurological health outcomes only. ^bMacEwen and Vernot^35–38 reported overlapping datasets with Bruner et al,³⁹ Kinkead et al,⁴⁰ Mattie et al,⁴¹ Gaworksi et al,⁴² and MacEwen and Vernot⁴³ for all neurological health outcomes; therefore, these articles did not undergo study quality evaluation. ^cMattie et al⁴⁴ had an overlapping dataset with Fetcher et al⁴⁵ for all neurological health outcomes; therefore, this article did not undergo study quality evaluation. ^dMacEwen and Vernot⁴⁶ had a partially overlapping dataset with Bruner et al³⁹ and Gaworski et al⁴² for some neurological health outcomes; this article underwent study quality evaluation for unique neurological health outcomes only. ^eMacEwen and Vernot⁴³ had a partially overlapping dataset with MacEwen and Vernot,⁴⁷ and Mattie et al⁴¹ for some neurological health outcomes; this article underwent study quality evaluation for unique neurological health outcomes only. ^fMacEwen and Vernot⁴⁷ had a partially overlapping dataset with Bruner et al,³⁹ Kinkead et al,⁴⁰ Mattie et al,⁴¹ Gaworski et al,⁴² and MacEwen and Vernot⁴³ for some neurological health outcomes; this article underwent study quality evaluation for unique neurological health outcomes only. ^gDodd⁴⁸ had an overlapping dataset with MacMahon et al⁴⁹ for all neurological health outcomes; therefore, this article did not undergo study quality evaluation. ^hNordholm et al⁵⁰ had a partially overlapping dataset with MacMahon et al⁴⁹ for some neurological health outcomes. However, for all measurements of neurotransmitter levels and neurobehavioral tests, MacMahon et al⁴⁹ and Dodd⁴⁸ overlapped with Nordholm et al.⁵⁰ Nordholm et al⁵⁰ underwent study quality evaluation for unique neurological health outcomes only. ⁱMattie et al⁵¹ had an overlapping dataset with Sterner et al⁵² for all neurological health outcomes; therefore, this article did not undergo study quality evaluation. ^jMattie et al⁵³ had an overlapping dataset with Sterner et al⁵⁴ for all neurological health outcomes; therefore, this article did not undergo study quality evaluation. ^kSterner et al⁵⁵ had an overlapping dataset with Wong et al⁵⁶ for all neurological health outcomes; therefore, this article did not undergo study quality evaluation.

Epidemiologic, animal toxicological, and mechanistic studies provide insight into the complex processes that mediate neurologic effects following jet fuel exposure. Humans and animals exposed to jet fuels demonstrated functional neurologic alterations and deficits that were corroborated by cellular and molecular findings. The following results are presented in an order that represents the degree to which jet fuel exposures were associated with adverse neurologic health effects, with the most robust evidence described first.

Sensory Outcomes

This review identified effects on the neurosensory system following jet fuel exposure, including auditory dysfunction and ocular conditions. Epidemiologic and animal toxicological study characteristics and summary findings are presented in Supplemental Digital Content, Supplementary Table S1 (http://links.lww.com/JOM/C277) and Supplementary Table S2 (http://links.lww.com/JOM/C278), respectively. Mechanistic study characteristics and summary findings are presented in Supplemental Digital Content, Supplementary Table S3 (http://links.lww.com/JOM/C279).

Auditory Effects

Among the neurologic outcomes reviewed, the most compelling evidence is for ototoxicity following jet fuel exposure. Epidemiologic studies assessed jet fuel exposure alone or with noise as a co-exposure, which frequently occurs in occupational or military settings. Several studies assessing jet fuel exposure alone reported associations with hearing loss; however, the results were mixed, some were descriptive only (ie, lacking statistical comparisons), and there was a paucity of epidemiologic data.

Four epidemiologic studies examined the relationship between jet fuel exposure and hearing loss. In a cross-sectional study, Kaufman et al observed a significant association between exposures to jet fuel and noise and persistent hearing loss in workers at a US Air Force (USAF) installation following exposure to jet propellent (JP)-4.⁵⁸ Miko et al assessed results of a community survey following the accidental release of JP-5 into the Joint Base Pearl Harbor-Hickam (JBPHH) water distribution system, noting that 23% of adults and 7% of children surveyed reported ringing in the ears, and among those individuals, 67% of adults and 51% of children reported symptoms persisting for 30 days or more.⁵⁹ A cohort study in Swedish industrial workers observed abnormal cortical frequency glides, which may be indicative of auditory pathway lesions, in four of eight study participants and interrupted speech discrimination in three of eight participants among the exposed workers.⁶⁰ In addition, a case series reported long-term hearing impairment in a warehouse worker determined by audiometric tests following JP-8 inhalation exposure.⁶¹

A number of studies also investigated associations of jet fuel exposure in combination with noise.^{31,32,62–64} Fuente et al assessed audiometric thresholds, as well as distortion product otoacoustic emissions (DPOAE), a measure of preneural auditory dysfunction related to cochlear hair cells.⁶² The study reported significant hearing threshold impairments, suggesting peripheral auditory dysfunction in Royal Australian Air Force personnel exposed to JP-8 and noise compared to unexposed personnel. Fuente et al also assessed central auditory function using auditory brainstem response (ABR) measurements and behavioral techniques that examined compressed speech and words-in-noise tests, but no central auditory impairments were observed.⁶² A cross-sectional study by Mattie et al noted significant differences in audiological testing results among USAF and Japan Air Self-Defense Force flight line personnel compared to unexposed referents, but results were not consistent.^31,32 Differences included increased audiological immittance at some frequencies among T-4, F-2, and F-16 flight line personnel; decreased otoacoustic emissions at some frequencies among T-4 and F-2 exposed personnel; and differences in ABR among T-4, F-16, and F-15 exposed personnel. Dreisbach et al also reported increased hearing difficulties in US military personnel exposed to JP-5 and noise compared to those who were exposed to noise only at Marine Corps Air Station Miramar, although these differences were not statistically significant.⁶³ A review evaluating human exposure to jet fuel or aromatic solvent components in tandem with noise observed a positive association with central auditory dysfunction/hearing loss.⁶⁴

Several animal toxicological studies were designed to assess the effects of jet fuels with occupational co-exposures, such as noise, in mind, with suppression of DPOAEs indicating impaired sensitivity of the cochlear hair cells and peripheral auditory dysfunction. In the three separate studies, Fechter et al⁶⁵ assessed effects of JP-8 on DPOAE. Fechter et al exposed rats to JP-8 for different durations, and half of the animals were also subjected to noise (97 or 105 dB).⁶⁵ Results suggested that JP-8 produced permanent DPOAE alterations, as JP-8 enhanced noise-induced DPOAE amplitude impairment 4 weeks following exposure. In another study, Fechter et al (exposed rats to either JP-8 or Fischer-Tropsch (FT; a synthetic jet fuel) jet fuel with or without noise exposure (100–102 dB).⁶⁶ The authors reported no exposure-related effects on DPOAE after exposure to FT alone or in combination with noise. In contrast, JP-8 alone transiently suppressed DPOAE amplitudes, but this loss did not reach statistical significance; however, groups exposed to both JP-8 and noise showed significant short- and long-term DPOAE response impairment. In a third study, Fechter et al exposed rats to JP-8 and/or constant nondamaging noise (85 dB) and observed Impaired DPOAE amplitudes at 4 weeks postexposure in all JP-8 exposure groups.⁴⁵ In the same study, when rats were exposed to JP-8 and intermittent noise (102 dB), the exposed group exhibited significant short- and long-term reductions in DPOAE amplitude.⁴⁵ No effects on DPOAE were observed in rats exposed to jet fuel alone,^45,65 and no adverse effects on DPOAE were reported in other studies that exposed rats to JP-8 with or without concurrent noise exposure.^67–70

To evaluate cochlear hair cell death following jet fuel and/or noise exposures, cochlear histopathology was conducted in rat models. Jet fuel exposure alone had no effect on outer hair cell death^67,68,70; however, several studies reported marked changes in outer hair cell death when jet fuel and noise exposures were combined.^45,65 For example, Fechter et al⁶⁵ reported increased outer hair cell death in male rats exposed to JP-8 and noise. Similarly, Fechter et al⁴⁵ reported that rats exposed to JP-8 and intermittent noise exhibited greater rates of outer hair cell death compared to control animals. Rats exposed to noise alone, however, did not demonstrate an increase in outer hair cell death.^45,65 One study evaluating middle ear histopathology reported null findings after petroleum- or shale-derived JP-5 exposure.³³ Notably, Lin et al observed enriched expression of genes related to cell death and apoptosis in whole brains from rats exposed to JP-8.⁷¹ In addition, Sterner et al reported increased rates of cell death in three different auditory cell lines exposed to JP-8 for 24 hours.⁷² Overall, these data suggest that JP-8 is cytotoxic to cells involved with auditory function.

Many studies used audiometric threshold assessments to directly measure the neural output from the cochlea to the brain in rats. These tests record compound action potentials (CAPs), which are markers of synchronous action potentials from the auditory nerve. Exposure to jet fuel alone did not cause significant alterations in CAPs. However, Fechter et al reported that exposure to JP-8 and simultaneous, constant, or intermittent noise resulted in significant CAPs elevation.⁴⁵ Another study reported that JP-8 exposure followed by moderate noise exposure also significantly increased CAP.⁶⁵ In contrast, Fechter et al exposed male rats to JP-8 or FT jet fuel with or without noise exposure and observed no effects on CAPs.⁶⁶

ABR, which consists of five waves (W) evoked in response to auditory stimulation, assesses peripheral cochlear nerve function. In rats, the first wave (W_I) is generated from the peripheral cochlear nerve. No significant effects of jet fuel exposure with or without noise exposure on W_I of the ABR were observed.^67–70,73

In another study, Guthrie assessed neural adaptation, which is the refraction of the auditory nerve that occurs in response to changes in stimulus presentation speed.⁷⁴ The response amplitudes to a slow stimulus and a fast stimulus were measured, and the ability of the auditory nerve to modify its response after a change in stimulus presentation rate was determined. JP-8 and subototoxic noise exposures resulted in impaired adaptation, but this was not seen in rats exposed only to JP-8. Guthrie concluded that combined exposure to JP-8 and subototoxic noise resulted in abnormal neural adaptation that may be attributed to reduced efficiency of the peripheral auditory system.⁷⁴

Central auditory function has also been assessed in animals exposed to jet fuels and/or noise. Several studies analyzed the effects of jet fuel exposure on Waves II, III, IV, and V (W_II–V) of the ABR, which are measures of central auditory function. Guthrie et al exposed rats to JP-8 with or without a subototoxic noise level.⁶⁷ Rats exposed to jet fuel alone exhibited compressed response growth of W_II and W_III, indicating central auditory processing dysfunction (CAPD) in the brainstem. The group exposed to both JP-8 and noise displayed similar changes. The authors concluded that jet fuel exposure alone and in combination with noise may suppress neurotransmission signal amplification in the brainstem. Likewise, Guthrie et al exposed rats to JP-8 with or without a subototoxic noise level.⁶⁸ Simultaneous evaluation of neurotransmission in the peripheral (W_I) and central (W_II and W_III) auditory pathways was conducted to differentiate between peripheral and central dysfunctions. There were no exposure-related differences for W_I or W_II; however, exposure to JP-8 with or without noise caused significant amplitude reductions and temporal delays in W_III, indicating central auditory nervous system dysfunction in the upper portion of the brainstem. In another study, Guthrie et al exposed rats to JP-8 with or without a subototoxic level of noise.⁷³ Alterations in amplitude and latency for W_II and W_III, but not W_I, W_IV, or W_V, were observed in the combined exposure group. These abnormal brainstem circuit properties suggest that combined exposure to JP-8 and a nondamaging level of noise may modify caudal but not rostral brainstem circuit properties, indicating degeneracy of the auditory brainstem circuitry.

In another study, Guthrie et al examined central auditory functioning by measuring slow vertex potentials (SVPs).⁶⁹ Alterations of the SVP response time and magnitude of its components indicate changes in neural conduction time and neural activity following an auditory stimulus. Guthrie et al exposed rats to JP-8 with or without a subototoxic noise level and observed nonsignificant reductions in SVP magnitude in animals exposed to JP-8 alone.⁶⁹ Significant SVP magnitude reductions and latency increases were observed in animals exposed to JP-8 and noise, indicating inhibited brain responsiveness to auditory stimuli and signal transmission deficits.

Several studies have investigated the ototoxic mechanisms that may underlie the functional adverse effects of jet fuel exposure. For example, alterations of serotonin (5-HT) and/or the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in serum and the brainstem⁵⁰ and of 3,4-dihydroxyphenylacetic acid (DOPAC, a metabolite of dopamine) in the brainstem^75,76 were observed in rats exposed to JP-5 or JP-8. Such changes align with dysfunction of central auditory processing, which is modulated by the serotonergic and dopaminergic systems. Further, two studies demonstrated changes in expression of key genes related to neurotransmitter secretion in JP-8-exposed animals.^71,77 Specifically, rats exposed to JP-8 showed alterations of gene expression for Syntaxin 2 (Stx2), Syntaxin 7 (Stx7), and synaptosome-associated protein 23 (Snap-23) genes in whole brains.⁷¹ Lin et al also demonstrated alterations in the expression of neuronal γ-aminobutyric acid (GABA) transporter (Gat2) and GABA transporter 3 (Gat3), which are linked to neurotransmitter secretion and receptor binding.⁷⁷ Altered expression of Gat2 and Gat3 may contribute to jet fuel-related deficits in neurotransmission and impaired responsiveness to auditory stimuli.

Jet fuel exposure may also increase oxidative stress that can impact auditory function. McGuire et al reported increased protein levels of glutathione S-transferase M1 (GSTM1), a biomarker of toxicant exposure and mediator of oxidative stress, in JP-8-exposed animals.⁷⁸ However, Sterner et al reported JP-8 exposure decreased glutathione (GSH) levels in vitro,⁷² whereas other studies observed no changes in levels of GSH in vivo.^65,79 Thus, in addition to serotonergic and dopaminergic changes, effects on oxidative stress and cell death may contribute to the ototoxic effects of jet fuel exposure, such as impaired neurotransmission, abnormal neural adaptation, and degeneracy of the auditory brainstem circuitry.

Visual

Studies that evaluated ocular disorders following jet fuel exposure have produced mixed results. Several studies reported eye irritation symptoms among airplane mechanics,^27–30 military personnel,⁸⁰ and children and adults⁵⁹ following exposure to jet fuel. Odkvist et al reported abnormal ocular conditions in Swedish industrial workers, although no statistical comparisons were made.⁶⁰ Increases in weekly medical visits for mucosal membrane-related symptoms were reported among Department of Defense (DoD)–affiliated individuals throughout a 1-year observation period following the JP-5 water contamination event at JBPHH.⁸¹ These visits included both ocular (eg, ocular pain, eye lacrimation, and chemical conjunctivitis) and respiratory (eg, throat pain and chest pain with breathing) outcomes. A case series reported blurred vision in one of two warehouse workers following JP-8 inhalation exposure⁶¹; however, Tunnicliffe et al did not report any differences in watery eye symptoms in exposed airport workers.⁸² Several case reports^61,83–86 and reviews^87–89 describe mild-to-moderate eye irritation following jet fuel exposure.

Most findings from animal studies were consistent with the epidemiologic data, further demonstrating symptoms of eye irritation. For example, gross observations in rats exposed to Swedish Biofuels (SB)-8,⁵² synthetic-8 fuel (S-8),⁵¹ or Gevo alcohol-to-jet (ATJ) synthetic paraffinic kerosene (SPK)⁵⁴ revealed increased levels of “crusty eyes,” which the authors noted was likely due to mild eye irritation. In some studies, chromodacryorrhea, or “red tears,” which are encrustations around the eyes due to stress-induced release of porphyrins from the Harderian glands, was observed in both exposed and control animals; the authors attributed these findings to stress rather than exposure.^54,56 Alternatively, an acute eye irritation test in rabbits found no evidence of irritation following exposure to JP-4, JP-7, JP-8, or JP-TS.⁴³

Several studies investigated the impact of jet fuel exposure on eye and optic nerve histopathology. A 1-year inhalation study on mice revealed an increased occurrence of cataracts and keratitis after JP-7 exposure.⁴⁰ The same study assessed JP-TS exposure in mice and reported that females exhibited a higher incidence of cataracts and keratitis than males. Increased expression of the antioxidant enzyme GSTM1 was also observed in mouse retinas in response to inhalation of JP-8 + 100.⁷⁸ All other studies reported borderline changes in background lesions or no exposure-related effects.^{44,52,54–56,90}

Other histopathological findings did not support an association between jet fuel exposure and ocular effects. Histopathological examinations in animals generally observed mild⁵² or incidental^54–56 increases in Harderian gland inflammation. No significant exposure-related effects on the lacrimal and tarsal glands were observed.^{44,54–56,91}

Neurologic Outcomes

This review identified neurologic outcomes following jet fuel exposure, including adverse effects on memory, motor activity and coordination, general neurologic function, and the peripheral nervous system. Epidemiologic and animal toxicological study characteristics and summary findings are presented in Supplemental Digital Content, Supplementary Table S4 (http://links.lww.com/JOM/C280) and Supplementary Table S5 (http://links.lww.com/JOM/C281), respectively. Mechanistic study characteristics and summary findings are presented in Supplemental Digital Content, Supplementary Table S3 (http://links.lww.com/JOM/C279).

Memory

Five primary epidemiologic studies evaluated associations between jet fuel exposure and memory impairment, reporting mixed findings. In one study, performance on a memory test was significantly decreased among a group of active-duty USAF personnel following exposure to a high level of jet fuel compared to a lower exposure group.^25,26 Self-reported forgetfulness or difficulty remembering was reported in populations that handled or came into contact with jet fuels, including civilians (both adults and children) present during the jet fuel release into the water distribution system at JBPHH,⁵⁹ as well as in Swedish aircraft fuel system mechanics.⁹² Notably, difficulty remembering was persistent in the civilian population exposed to jet fuel via contaminated water at JBPHH, with a large proportion of children (73%) and adults (75%) reporting their symptoms of memory impairment lasting more than 30 days.⁵⁹ Other studies utilizing memory impairment tests did not observe significant differences between jet fuel-exposed groups and unexposed groups.^30,80

Regarding the effects of jet fuel exposure on memory in rodent models, several studies used the Morris water maze (MWM),^76,93,94 a test of hippocampal-modulated spatial learning and memory. All of these studies reported no exposure-related differences on probe trials (a measure of reference memory) in rats following exposure to JP-8, JP-5, Jet A, or FT.^93,94 In addition, rats exposed to JP-5 or JP-8 did not display alterations in memory consolidation, as measured by the passive avoidance test.⁷⁶

Motor Activity and Coordination

The findings regarding associations between occupational jet fuel exposure in humans and alterations in motor performance were mixed. Evidence was reported from three studies examining clinical signs and performance on simple reaction time, finger tapping, the grooved pegboard test, and the Santa Ana form board.^26,30,81 Heaton et al²⁶ observed better performance on the grooved pegboard test among the jet fuel-exposed groups, but it is possible that this improvement was, at least in part, due to practice effects. Knave et al³⁰ observed no significant differences in manual dexterity of Swedish aircraft mechanics exposed to jet fuels and an unexposed, control group. The study noted that the exposed and unexposed groups were similar, but those in the unexposed group consumed more alcohol. One study observed no difference in weekly medical visits with central nervous system (CNS) diagnoses, including gait disturbances, among cohort members following an accidental release of JP-5 into the water system at JBPHH compared to the preevent observation period. CNS diagnoses additionally included concentration, dizziness and giddiness, lethargy and fatigue, headache, and migraines.⁸¹

On the contrary, supplemental evidence supplied by reviews and case studies or case reports reported changes in motor performance. The Air Force Institute for Operational Health's (AFIOH) risk assessment on short-term JP-8 exposure reported that high-exposure individuals exhibited significantly decreased performance on a hand tapping test.⁹⁵ The assessment also reported a positive, nonsignificant association between exposure to jet fuel and self-reported frequency of “trouble gripping things.” Other studies also reported altered reaction time following JP-8 exposure,¹¹ impairment of fine motor skills in aircraft personnel exposed to jet oil emissions,⁹⁶ incoordination following jet oil emissions exposure in a military pilot,⁹⁶ and symptoms of ataxia and a “wobbly sensation” in 12 airmen conducting fuel cell repair without personal protective equipment (PPE).⁸⁴

Animal studies have reported jet fuel exposure–related impacts on motor activity and/or coordination. Gevo ATJ SPK–exposed rats demonstrated a significant increase in total active time and a trend toward increased rearing behavior.⁵⁴ Similarly, 90 days of SB-8 exposure resulted in increased rearing and a trend toward increased total motor activity.⁵² Likewise, Baldwin et al reported significant increases in arousal, activity, and rears.⁹⁴ Baldwin et al observed significantly increased ambulation following 5 and 20 days of JP-8 exposure and an increase in rearing behavior, which reached statistical significance at 20 days.⁹⁷ The authors noted hyperarousal and decreased habituation in the JP-8-exposed animals compared to unexposed controls.⁹⁷ Bogo et al also observed a significant increase in daytime home cage activity in rats following an acute oral exposure to petroleum-derived JP-5, although the authors attributed this increased activity to gastric irritation.³³ Additionally, Rossi et al reported increased grip strength in rats exposed to JP-5, noting that this effect could be a result of increased CNS activation.⁷⁶

In contrast to increased motor activity, Nordholm et al observed that JP-4–exposed rats demonstrated hypoactivity compared to controls after a 60-day, postexposure, recovery period, although both grip strength and treadmill fatigue tests revealed no differences between JP-4–exposed and control rats.⁵⁰ Mattie et al reported that male and female S-8–exposed rats exhibited decreased exploratory activity (eg, rearing) when compared to controls. Decreased ambulation and total movement were also observed in male rats exposed to S-8.⁴⁴ Bogo et al³³ reported that animals exhibited significantly higher overnight home cage activity following gavage with either petroleum- or shale-derived JP-5. Activity in the petroleum-derived group returned to normal the next day, whereas shale-derived JP-5–exposed rats showed significantly reduced movement for the remainder of the 7-day study.³³ However, no effects of petroleum- or shale-derived JP-5 were observed on overnight home cage activity following inhalational exposure in male rats.³³ JP-8–exposed animals also demonstrated a nonsignificant decrease in performance on the rotarod test when compared to unexposed controls,⁹⁷ whereas no rotarod performance differences were observed following exposure to petroleum- or shale-derived JP-5.³³ However, no significant impacts on motor activity were observed following exposure to hydroprocessed ester and fatty acid jet fuel (HEFA-C),⁵⁶ JP-5, or JP-8⁷⁶ in rats.

Data from mechanistic studies that investigated the adverse effects of jet fuel exposure on the brain helped to elucidate potential mechanisms of exposure-induced alterations on motor activity. One study reported an altered abundance of microRNAs (miRNA; 21–23 nucleotide long noncoding RNAs) in the cerebellum of rats following a 28-day exposure to several different jet fuels, although these changes did not correspond to transcript alterations.⁹⁸ Multiple studies have reported significant alterations in cerebellar neurotransmitter levels following jet fuel exposure, including decreased DOPAC⁷⁶ and increased 5-HT and 5-HIAA.^17,50 One study investigated inflammatory cell signaling responses in the cerebellum of rats following a 7-day dermal exposure to JP-8.⁹⁹ The authors found alterations in nuclear factor κB (NF-κB) and heat shock protein (HSP) pathways, both of which are key regulators in inflammatory responses.⁹⁹ Functionally, Rohan et al also observed a decrease in electrical activity in neurons in the cerebellum following jet fuel exposure, although this decrease was not statistically significant.⁹³ Another study observed that, after chronic jet fuel exposure, female rats displayed an increased incidence of vascular encephalopathy in the cerebellum that persisted for 1 year after exposure.⁴⁰ In addition to these cerebellar alterations, altered DOPAC levels have been observed in the brainstem following jet fuel exposure.^75,76 Taken together, these observations point to the potential exposure-induced mechanistic disruption of the cerebellum, as well as disruption of dopaminergic signaling in the brainstem, which could play a role in the dysregulation of motor coordination observed in jet fuel-exposed animals.

Several animal studies measured muscle tone and/or autonomic control as part of the functional observational battery (FOB) assessment. Aside from the increased grip strength observed in jet fuel-exposed animals in Rossi et al,⁷⁶ no differences in muscle tone were reported between exposed and control animals.^{44,52,54,56,97} Baldwin et al reported an effect on the autonomic nervous response (specifically, increased frequency of urination in rats following JP-8 exposure) but noted that there were no recorded instances of urination in the control animals during the observation period.⁹⁷ In that same study, exposure to JP-8 also resulted in increased fecal boli compared to control rats.

Vestibular Function

Three primary epidemiologic studies investigated vestibular effects associated with long-term exposure to jet fuel and reported mixed results. Smith et al observed significant increases in postural sway length and angular area in USAF personnel from JP-8–exposed work sites compared to unexposed individuals.¹⁰⁰ When benzene concentration was used as a measurement of cumulative jet fuel exposure, a significant positive association was observed with postural sway length; however, associations between other air sample–based indicators of cumulative jet fuel exposure and postural sway test results were mixed. In contrast, Maule et al reported no significant differences in total angular area or mean path velocity of postural sway between two different JP-8 exposure groups of USAF active-duty personnel; however, active-duty USAF personnel consistently exhibited better postural sway performance compared to the test reference values, which may reflect the healthy worker effect.¹⁰¹ Odkvist et al reported no increase in the occurrence of coordination abnormalities or other vestibular abnormalities in jet fuel–exposed Swedish aircraft mechanics; however, the study did not include an appropriate control or comparison group.⁶⁰

Several secondary sources also established incidences of vestibular disturbances in individuals exposed occupationally to jet fuels in short-term^95,102,103 and long-term⁶¹ exposure scenarios. The AFIOH final risk assessment for short-term JP-8 exposure reported a significant association between JP-8 exposure and postural sway.⁹⁵ Similarly, several case reports identified vertigo-like symptoms in military personnel after acute exposure to jet fuel.^61,102,103

General Neurologic Symptoms

Epidemiologic studies also reported on general neurologic symptoms following short-term and long-term jet fuel exposures. For instance, several studies reported increased incidence of headaches or migraines presumed to result from short-^{30,92,104,105} and/or long-term^30,92 exposure to jet fuels. A case study and various case series reports observed headache symptoms in some proportion of exposed personnel following short-^59,84,85 or long-term⁶¹ jet fuel exposures. One study of community members present during the accidental JP-5 release into the water distribution system at JPBHH reported an increased risk of migraines compared to a cohort of DoD-affiliated individuals at a comparison base.¹⁰⁵ Conversely, one records-based event analysis observed no difference in weekly medical visits for CNS diagnoses, including headaches and migraines, among community members near JBPHH,⁸¹ and three studies reporting on occupational exposure to jet fuels observed no differences in self-reported headaches or chronic pain between exposure groups.^80,95,104

Among the general neurological symptoms assessed in humans, several studies reported on fatigue, sleep disturbances, and/or dizziness. Bell et al conducted a randomized study of Gulf War–era veterans exposed to clean air or to low levels of JP-8 fuel fumes in a controlled environment to evaluate symptoms of chronic fatigue.¹⁰⁶ Following exposure, chronic fatigue was evaluated using performance on a computerized test, with jet fuel–exposed participants exhibiting faster peripheral reaction times than controls; however, the study authors indicated that this may have reflected sensitization from prior exposure. Decreased weekly medical visits for behavioral syndromes with physical factors (eg, sleep disorders) were observed among community members near JBPHH; however, this diagnostic category was broad and included social and emotional behavior conditions (eg, eating disorders and post-partum depression) that might compromise sensitivity.¹⁰⁷ Following long-term exposure to jet fuels, fatigue, dizziness, and/or sleep disturbances were more frequently reported by exposed Swedish aircraft mechanics compared to less heavily exposed⁹² or unexposed³⁰ individuals. No differences in dizziness were observed in a study of civilians exposed to JP-8 from the Hill Air Force Base in Utah.⁸⁰ In a civilian population experiencing short-term exposure to JP-5 in drinking water at JBPHH, Miko et al reported the prevalence of several neurologic symptoms, including fatigue (52% in adults, 27% in children), dizziness (46% in adults, 21% in children), sleep disturbance (39% in adults, 18% in children), loss of consciousness (3% in adults, 2% in children), and seizures (1% in adults, 1% in children).⁵⁹ In most cases, symptoms persisted after 30 days. No difference in weekly medical visits for CNS symptoms, including dizziness, giddiness, lethargy, and fatigue, was observed in community members near JBPHH following the accidental JP-5 release compared to the preevent observation period. Other symptoms included in the CNS analysis included concentration impairments, gait disturbances, headache, and migraines.⁸¹

Supplemental information provides additional support for neurologic symptoms. Case reports and case series following short-term exposures to jet fuels in military aviators,⁸⁵ Air Force pilots,¹⁰⁸ a military refueler,⁶¹ and two exposed warehouse workers⁶¹ all reported general neurologic symptoms, including slurred speech, intoxication, fatigue, loss of consciousness, disorientation, dizziness, and/or fatigue. Secondary sources that reported the incidence of several neurologic outcomes also indicated dizziness, sweating, fatigue, exhaustion, lethargy, and changes in neurologic function.^{11,83,87,88,95,96,109–112}

Peripheral Nervous System

Numerous studies evaluated the effects of jet fuel exposure on the peripheral nervous system (PNS) and reported mixed findings. Symptoms of PNS impacts include tremors, numbness, polyneuropathy (a clinical condition impacting peripheral nerve function, characterized by symptoms such as tingling, weakness, and numbness),¹¹³ and/or neurasthenia (broadly defined by weakness and fatigue).¹¹⁴ Evidence of polyneuropathy following exposure to jet fuels was observed in studies of Swedish aircraft fuel system mechanics, which reported greater incidence of self-reported polyneuropathy symptoms compared to less heavily exposed⁹² and unexposed comparison groups.³⁰ Peripheral nerve damage was reported in heavily exposed workers, evidenced by increased reports of muscular atrophy and hand/finger paresis; however, nerve conduction velocity testing revealed no differences between the two exposure groups.⁹² A large proportion of exposed mechanics exhibited symptoms (n = 12/30) and signs (n = 18/30) of polyneuropathy during a physical examination, but symptoms of polyneuropathy were also observed during examination in the control groups, although they rarely reported experiencing such symptoms. No difference in the number of incident peripheral neuropathy cases was observed among community members exposed to JP-5 release in contaminated water at JBPHH compared to unexposed individuals.¹⁰⁵ Increased rates of tremors and numbness were reported in personnel highly exposed to JP-8 in an AFIOH risk assessment.⁹⁵

Some studies noted the absence of PNS effects with jet fuel exposure. No differences were observed in numbness or tingling of the hands after 6 or 18 months of exposure to jet fuels among workers exposed to jet fuels at the Hill Air Force Base.⁸⁰ Similarly, nonsignificant increased rates of tremors and numbness were found in personnel highly exposed to jet fuel in an AFOIH risk assessment.⁹⁵

In addition to the clinical symptoms reviewed previously, several epidemiologic and animal toxicological studies investigated jet fuel exposure–induced alterations to stimulus response, including vibration, nociceptive, and reflex responses. Knave et al reported that heavily exposed Swedish aircraft mechanics demonstrated no significant difference in vibration sensation thresholds.⁹² Reduced nociception, or the detection of painful stimuli, was reported in a case study describing a pilot exposed to JP-4 vapor leakage into the cockpit during a flight.¹⁰² Evidence from one rodent study demonstrated an altered response to nociceptive stimuli, in which rats exhibited decreased latency in the tail flick response (TFR) to a heat stimulus following 14 days of inhalation exposure to JP-4 and a 60-day recovery.⁵⁰ However, the rats did not exhibit a decrease in tail flick latency after a 14-day recovery. Another rodent study conducted by Rossi et al reported no significant differences in TFR between control rats and rats exposed to JP-5 or JP-6 after a 65-day recovery period.⁷⁶ Additionally, acute exposures to JP-10 resulted in no observable differences in the measured reflex responses (ie, flexor, extensor thrust, tonic neck, righting, placing) of Beagle dogs across 28 days of postexposure observation.⁴⁶

Sensory-Related Behaviors

Sensory-related behaviors were reported in some of the studies that were reviewed.^50,76,115 In a rat study investigating the acoustic startle response (ASR) and prepulse inhibition (PPI), exposure to JP-4 for 14 days resulted in a decreased PPI response following a 60-day recovery.⁵⁰ This alteration in PPI was consistent with the observed changes in cerebellar, brainstem, and cortical 5-HT concentrations, as the serotonergic system modulates sensorimotor function. However, in rats exposed to JP-5 or JP-8 for 6 weeks, no significant changes in ASR or PPI were observed following a 65-day recovery.^76,115 Finally, Nordholm et al reported no significant differences in photosensitivity between control rats and rats exposed to JP-4 for 4 weeks following 14 or 60 days of recovery.⁵⁰

Cognitive and Behavioral Outcomes

This review identified effects on cognitive and behavioral outcomes following jet fuel exposure, including attention, executive function, and general cognition; visuospatial performance; and social and emotional behavior. Epidemiologic and animal toxicological study characteristics and summary findings are presented in Supplemental Digital Content, Supplementary Table S6 (http://links.lww.com/JOM/C282) and Supplementary Table S7 (http://links.lww.com/JOM/C283), respectively. Mechanistic study characteristics and summary findings are presented in Supplemental Digital Content, Supplementary Table S3 (http://links.lww.com/JOM/C279).

Attention, Executive Function, and General Cognition

Numerous primary studies have examined the impact of jet fuel exposure on different aspects of cognition, such as attention and executive functioning. Attention was evaluated using test instruments assessing reaction time and impulsivity, such as the Continuous Performance Test (CPT) or divided attention tasks. A significantly decreased reaction time was observed during the six-month evaluation in an 18-month study of the transition from JP-4 to JP-8 fuel use; however, no associations were observed at other time points.⁸⁰ No changes in reaction time were observed in other studies that evaluated attention,^26,30,116 but two studies reported an increased number of errors or premature responses, suggesting greater impulsivity in JP-8–exposed personnel.^26,116

Two studies examined concentration and observed mixed findings. Miko et al observed difficulty concentrating among 38% of adults surveyed, with 72% of those adults reporting symptoms lasting 30 or more days after exposure to water contaminated with JP-5.⁵⁹ This study also reported difficulty concentrating among 20% of children surveyed, and 70% of those children reported symptoms persisting for 30 or more days. A medical records–based analysis of community members at JBPHH observed no difference in weekly visits for CNS diagnoses, including difficulty concentrating, following the accidental JP-5 release into the water distribution system when compared to the preevent observation period.⁸¹ Supporting evidence from the AFOIH risk assessment showed that jet fuel–exposed, active-duty, Air Force personnel were 2.5 to 3.4 times more likely to report trouble concentrating compared with unexposed workers.⁹⁵

Four primary epidemiologic studies evaluated the association between jet fuel exposure and executive function using computerized (eg, MicroCog test) and noncomputerized (eg, Bourdon-Wiersma test) tests, with mixed findings. Time to complete executive function tasks was significantly longer in workers exposed to JP-8 at the Warfield Air National Guard Base¹¹⁶ and Swedish aircraft fuel system mechanics³⁰ compared to unexposed groups. Tu et al also reported reduced accuracy on executive function tests among the exposed group.¹¹⁶ No significant changes in executive function were observed in two studies of civilians and USAF personnel stationed at Air Force bases^26,80; however, the results in these studies may have been impacted by practice effects.²⁶

Effects of jet fuels on executive function have also been assessed in animals. One animal study investigated the effects of JP-8 on various operant conditioning tasks of increasing difficulty in rats.⁷⁵ The authors noted that the rats exposed to JP-8 consistently exhibited deficits on tasks of moderate or greater difficulty. For instance, in the stimulus reversal and incremental repeated acquisition (IRA) phases, rats exposed to JP-8 earned fewer reinforcers and had lower percentages of correct responses than control animals, suggesting impairment in the ability to learn and/or perform tasks of high complexity. It is important to note, however, that these differences did not reach statistical significance. Rats exposed to jet fuels have been shown to exhibit changes in dopamine and 5-HT levels in the cerebral cortex and striatum, which are regions related to executive functioning and attention regulation.⁵⁰ In addition, Lin et al and Lin et al demonstrated that in vivo jet fuel exposure in rats resulted in altered expression of genes related to neurotransmitter secretion and receptor binding in whole brain tissue.^71,77 Furthermore, epigenetic changes, specifically in miRNA levels in the hippocampus and prefrontal cortex in rats following jet fuel exposure,⁹⁸ provide additional support for neurologic effects that may impact memory, attention, and different characteristics of executive functioning.

Four primary epidemiologic studies provided mixed evidence on the association between jet fuel exposure and cognitive function^80,116 and symptoms.^59,107 Tu et al administered a dual task that evaluates multiple facets of cognitive function and reported significantly increased response time paired with a significant decrease in accuracy in JP-8–exposed personnel, indicating impaired cognitive function.¹¹⁶ In contrast, Olsen et al administered tests of neurocognitive function (eg, reasoning, calculation, and proficiency) in a cohort study conducted before and after the transition from using JP-4 jet fuel to JP-8 at the Hill Air Force Base.⁸⁰ There were no differences between the exposed and unexposed groups at any time point during the fuel transition phase (ie, from JP-4 to JP-8); however, the data suggested impaired cognitive functioning at baseline (while still working with JP-4). Regardless of exposure group, overall test performance between baseline and 18 months into the study significantly improved across all tests, suggesting a practice effect. In another study, confusion was reported by children (9%) and adults (23%) following the release of JP-5 into the JBPHH water distribution system, and 56% of children and 65% of adults who reported confusion noted that the persistence of this symptom for 30 or more days.⁵⁹ A medical records–based analysis of members of this community noted no difference in weekly visits related to mental disorders, intellectual disability, or schizophrenia at JBPHH when compared to the preevent exposure period.¹⁰⁷

Cognitive deficits after jet fuel exposure have also been observed in rats. Rohan et al examined rats exposed to JP-5, JP-8, Jet A, or FT jet fuel to determine whether exposure affected performance on the MWM test.⁹³ No adverse effects were reported for rats exposed to JP-5, JP-8, or Jet A. However, compared to control rats, the FT-exposed animals exhibited significantly longer latencies to reach the platform and longer distance traveled to reach the platform on learning days four and six, indicating subtle learning impairment.

Data from mechanistic experiments support the functional deficits reported in humans and animals. For example, jet fuels have been shown to induce neural cell death. Grant et al exposed an embryonic hippocampal cell line to JP-8 and reported that the rates of cell death differed by neural cell type, with glial cells being more vulnerable than hippocampal cells.¹¹⁷ Glial cells are important for various facets of neurologic health and provide support for critical nervous system functions by modulating nerve signal propagation, regulating neurotransmitter uptake, providing a physical scaffold for neural cell development, and preventing or aiding in recovery from neural injury. Lin et al also demonstrated that the expression of genes related to proteins involved in cell death and apoptosis was enriched following exposure to JP-8, indicating that this jet fuel is likely cytotoxic.⁷¹ However, the data on oxidative stress markers associated with exposure to jet fuel were mixed: McGuire et al observed an increase in protein levels of GSTM1 in mice exposed to JP-8 + 100,⁷⁸ whereas other studies reported no effects of jet fuel exposures on GSH levels in the brain.^65,79

Visuospatial Performance

Visuospatial performance was assessed in some studies of jet fuel–exposed cohorts and animals. Heaton et al assessed visuospatial performance across a work week in a group of activity-duty USAF personnel.²⁶ Although no differences were observed at baseline (ie, study day 1), there was a significant exposure-related decrease in visual organization across the work week. In contrast, other studies evaluating visuospatial performance (spatial processing)⁸⁰ or function (speed or accuracy)¹¹⁶ observed no differences between jet fuel–exposed workers compared to unexposed workers. Alterations of neurotransmitter concentrations in the hippocampus of rats exposed to different types of jet fuels indicated changes in the neurochemical milieu in brain regions that modulate various aspects of memory and visuospatial performance.^50,97

Social and Emotional Behavior

Depression and other social-emotional symptoms have been described in four primary epidemiologic studies examining jet fuel exposure among different populations. Depression persisting for 30 days or more was reported in 27% of adults and 6% of children who reported any depression following JP-5 exposure via contaminated water at JBPHH.⁵⁹ Further, anxiety, irritability, nervousness, and paranoia were reported in this study in 46%, 37%, 35%, and 12% of adults and 16%, 16%, 14%, and 4% of children, respectively. A medical records–based event analysis of individuals from this community observed no difference in weekly visits related to anxiety, mood disorders, and behavioral disorders following the JP-5 release at JBPHH versus the preevent observation period.¹⁰⁷ In occupational studies, reports of long-term depression or anxiety symptoms were described in a population of Swedish aircraft fuel system mechanics as a part of an assessment of neurasthenia.^30,92 These symptoms appeared to be more prevalent in the heavily exposed group compared to the less exposed group (based on job titles), and a similar pattern was observed comparing a jet fuel-exposed group to an unexposed group.^30,92

As social-behavior endpoints are difficult to assess in experimental animals, few studies attempted to examine the impact of jet fuels on these outcomes. One study observed a reduction in rearing in female rats following S-8 jet fuel exposure,⁴⁴ suggesting increased anxiety-like behavior. Another study examined sociability and depression-like behavior in male rats exposed to JP-5 or JP-8 but reported no significant effects in conspecific approach (sociability) or the Porsolt forced swim test (depression-like behavior) following exposure.⁷⁶ One study assessing behavioral observational profiles found no differences in aggressive behavior between control or male rats exposed to petroleum-derived JP-5.³³

Animal Nervous System Alterations

This review identified adverse effects on animal nervous system modifications following jet fuel exposure including brain weight, nervous system histopathology, and electrophysiology. Animal toxicological study characteristics and summary findings are presented in Supplemental Digital Content, Supplementary Table S8 (http://links.lww.com/JOM/C284). Mechanistic study characteristics and summary findings are presented in Supplemental Digital Content, Supplementary Table S3 (http://links.lww.com/JOM/C279).

Brain Weight

Nine rodent studies that examined the effects of jet fuel exposures on brain weight reported mixed results; however, the experimental design and jet fuel type used also varied among the studies. Following a 90-day exposure to S-8 jet fuel, significantly increased absolute (3%) and relative (1–8%) brain weights were observed in S-8–exposed female rats but not in males.⁴⁴ Study authors noted that female body weights were slightly but not significantly decreased, and they were unable to attribute the changes in brain weight to differences in body weight alone.

Sweeney et al conducted a 14-day study in two phases, the first in outbred Sprague-Dawley rats and the second in both Sprague-Dawley and inbred F-344 rats, to determine whether there were differences in sensitivity to Jet A exposure between the two strains.¹¹⁸ The animals' light/dark cycles were also reversed in the second phase. Increased absolute brain weight was only observed in the first phase at 24 hours but not at 7 or 14 days following the final exposure. Given the lack of exposure-related effects on brain weight in the second phase or at other time points, the authors declared the increased absolute brain weight a spurious observation. Similarly, a subacute study that exposed male Sprague-Dawley rats to JP-4 and assessed absolute and relative brain weights 14 or 60 days postexposure observed no significant effects.^48,49

In one 90-day study, male rats were exposed to JP-8, and relative brain weight significantly increased in all exposure groups.¹¹⁹ However, this effect was likely driven by concurrent decreases in body weight, as no effects on absolute brain weight were observed. Other studies that evaluated brain weight in rodents following inhalation to other types of jet fuel over a 90-day period (HEFA-C,⁵⁶ SB-8,⁵² Gevo ATJ SPK⁵⁴) reported no significant differences. Studies that exposed rodents to jet fuels via oral gavage for 90 days¹²⁰ or dermal application for up to 105 weeks¹²¹ also reported no significant exposure-related effects on absolute or relative brain weight.

Nervous System Histopathology

Several studies included histopathological evaluation of nervous system tissues in experimental animals following jet fuel exposure, with mixed results. A higher incidence of vascular encephalopathy was observed in the cerebellum, pons, and midbrain of rats exposed to both JP-TS and JP-7 for 1 year.⁴⁰ This finding was maintained in female rats chronically exposed to JP-TS or JP-7 after a 1-year recovery period. Three studies reported higher incidences of nonneoplastic lesions in the brains of jet fuel–exposed animals, including minimal mineralization in the cerebrum in male and female rats exposed to SB-8 for 90 days,⁵² calcification in female mice dermally administered JP-5 for 2 years,⁹¹ and focal mineralization in male mice observed 21 months after a 90-day exposure to JP-8,⁴¹ but these changes were not considered exposure related. Other studies included in this review did not observe exposure-related nonneoplastic lesions in the brain,^{33,34,39,42,44,54,56,90,118,120} spinal cord,^{40,44,54,56,90,91} sciatic nerve,^{33,39,40,42,44,56,91,120} or lateral saphenous nerve³³ following jet fuel exposure; however, these studies generally did not report quantitative data for histopathological outcomes.

Electrophysiology

One study used electrophysiology to assess the effects of jet fuels on neural stimulus integration, short-term neural plasticity, and spontaneous spiking frequency.⁹³ Alterations in these endpoints underscore the ability of jet fuels to impact neurotransmission and neural excitability, creating a basic framework for how these electrophysiological effects may translate into varied adverse neurologic symptoms. Rohan et al evaluated the differential effects of exposure for 4 weeks to JP-5, JP-8, Jet A, or FT jet fuel in rats.⁹³ Electrophysiological measurements were conducted in acute hippocampal brain slice preparations. Specifically, the dentate gyrus (the primary target of cortical input to the hippocampus) and/or CA1 (contains neurons that project to the principal output of the hippocampus) regions were assessed in animals exposed to jet fuels. These regions play critical roles in stimulus input integration and modulate the complex cellular and molecular processes involved in learning and memory consolidation.^122–124 When assessing neuron field responses in the hippocampus, small but statistically significant decreases in the amplitude of CA1 neuron field potentials were observed in rats exposed to FT and JP-5. However, no modifications were observed in the dentate gyrus region.⁹³

Rohan et al also assessed short-term neural plasticity using paired pulse stimulations.⁹³ A small but significant decrease in response in neurons within the dentate gyrus was observed in rats exposed to Jet A. A nonsignificant decrease was also observed with FT exposure. There were no changes in neural plasticity in the CA1 region with jet fuel exposures; however, the authors observed a nonsignificant decrease in spiking frequency in the CA1 region in rats exposed to Jet A, JP-5, and FT. The authors reported that the lack of significance was due to large variability among the animals in the same exposure groups. Within the dentate gyrus, a decrease in spiking frequency was observed following exposure to JP-5 and FT, although the decrease did not reach significance in the FT exposure group. Additionally, a nonsignificant decrease in spontaneous neural spiking frequency was also observed in the cerebellum following JP-5 exposure.

Alterations of electrophysiological endpoints are correlated with decrements in learning and memory. FT-exposed rats exhibited moderate learning impairment in the MWM test, as evidenced by increased latency to the platform and average swimming distance during training trials.⁹³ In addition, jet fuel–associated decreases in spontaneous spiking activity observed in the cerebellum, although not reaching significance, may lend mechanistic insight into alterations in motor activity and coordination observed following jet fuel exposures.^{44,50,52,54,76,93,97}

Bogo et al assessed somatosensory evoked potentials (SEPs) in animals during a 30-day inhalational exposure study on effects of shale-derived JP-5.³³ Electrodes were implanted over the right somatosensory cortex and right frontal sinus, and SEPs were recorded weekly. The authors reported no significant effects on the amplitudes, latencies, or intervals of SEP peaks.

DISCUSSION

Jet fuels are comprised of hundreds of hydrocarbons that, once in the body, can easily cross biological membranes, including the blood-brain barrier. It is well established that constituents of jet fuel exhibit neurotoxicity in humans, animals, and cell-based models. Because jet fuel exposure is a significant concern for military service members, it is imperative to better understand the potential neurotoxic consequences related to these exposures. The current review presents an overview of the many neurologic, cognitive and behavioral health effects associated with exposure to jet fuels across epidemiologic, animal, and mechanistic evidence streams.

The review incorporated recent evidence that increases confidence in the determination made in previous assessments that there is evidence for an association between jet fuel exposure and neurologic, cognitive, and behavioral health effects.^11,17,125 Similar findings have been reported in studies investigating the effects of exposure to kerosene (in the absence of additives typically present in jet fuel), although the majority of these studies have investigated the effects of exposure due to household kerosene use.^88,126 Additionally, this review identified recent studies providing novel epidemiologic evidence for hearing impairment,⁵⁸ memory impairment,^26,62 neurologic symptoms,⁵⁹ and adverse effects on attention and visuospatial performance in occupationally exposed individuals²⁶ and animal toxicological evidence for electrophysiological measurements,⁹³ auditory function and ototoxicity,^73,74 and cognitive performance.⁹³

Epidemiologic Data Summary and Synthesis

The primary epidemiologic data provided slight evidence that jet fuel exposure negatively impacts neurological health, leading to adverse neurologic health outcomes, including hearing impairment, ocular conditions, and memory impairment (Table 1 and Supplemental Digital Content, Supplementary Table S9, http://links.lww.com/JOM/C285).^20,21 This conclusion was based on considerable uncertainty related to the overall body of evidence and the fact that the evidence base consisted of primarily low confidence studies. Results for peripheral nervous system health outcomes and neuropsychological pain and discomfort indicated greater frequency of symptoms following jet fuel exposure, but data were limited to low confidence and uninformative studies. The types of neurological health outcomes assessed in these studies varied greatly, and statistical analyses were not always provided.

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 neurological health outcomes with considerable uncertainty; evidence was limited to a set of consistent low confidence studies.
Animal toxicological	Moderate	Primarily consistent evidence of an association between jet fuel exposure and neurological health 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 indicated that jet fuel exposure likely caused neurological health outcomes in humans, although there were outstanding questions or limitations that remain, and the evidence was insufficient for a higher conclusion level.

Hearing impairment following jet fuel exposure was observed in some studies, and one low confidence study reported coherent effects on vestibular function (Supplemental Digital Content, Supplementary Table S9, http://links.lww.com/JOM/C285). The structures within the ear and associated sensory neurons are essential for hearing and vestibular function, suggesting a coherent effect. One medium confidence study suggested apparent improvements among jet fuel–exposed Air Force personnel for vestibular function as compared to the reference population that had little to no jet fuel exposure.¹⁰¹ However, the study authors noted that the observed exceptional performance on measures of vestibular acuity may have been influenced by the younger age and high fitness level of the study population, as younger-aged persons are more likely to exhibit better agility and faster reflexes.¹⁰¹ In another medium confidence study, Air Force personnel with higher jet fuel exposure also displayed improved performance on tests of psychomotor speed and motor function compared to the low exposure group, but the authors suggested that practice effects from repeated testing may have influenced these findings.²⁶ Importantly, exceptional performance¹⁰¹ or practice effects²⁶ may have also impacted the ability to observe differences associated with jet fuel exposure in these populations.

Self-reported neurologic symptoms, including polyneuropathy and memory impairment, were elevated in studies of civilian subjects,^30,92 but these studies were frequently limited by ill-defined health outcome assessments. Observations from case reports support an increased frequency of neurologic symptoms following acute exposures to jet fuel exhaust. Studies in military settings frequently mitigated subjective interpretations or bias in test administration by utilizing standardized neuropsychological test instruments. Notably, performance on a memory test was decreased in a medium confidence study of personnel at levels of jet fuel exposure well below the USAF safety thresholds set for occupational jet fuel exposure.²⁶

There was slight evidence that jet fuel exposure negatively impacts cognitive and behavioral health, such as adverse impacts to attention, cognitive function, and visuospatial performance, as well as increases in the frequency of depression and anxiety symptoms and alterations of other social-emotional behavior and regulation symptoms (Supplemental Digital Content, Supplementary Table S9, http://links.lww.com/JOM/C285). Results were largely consistent across relevant endpoints. Two studies utilized standardized assessment instruments,^26,80 but there was additional uncertainty related to studies where health outcomes were not well defined. Practice effects from repeated testing may also have been observed in one medium confidence study, which suggested an improvement in executive function.²⁶

The adverse effects of exposure to kerosene, the major component of jet fuels, align with the body of evidence related to the potential health effects of jet fuel exposure. However, available literature on the health effects of kerosene in humans details exposure among women and children by accidental ingestion, dermal contact, and inhalation related to the residential use of kerosene for home heating or cooking.⁸⁸ Such exposure scenarios may have some relevance to occupational and environmental exposure through accidental spills and contaminated drinking water. Reviews of kerosene exposure reported neurologic and cognitive health effects.^{88,102,127,128} Acute exposures, such as accidental ingestion of kerosene, have reportedly resulted in irritability, restlessness, ataxia, drowsiness, convulsions, loss of consciousness, and death (believed to be secondary to hypoxia).^102,127,128 Reviews also noted sensory effects, including olfactory fatigue,^102,127 unusual tastes,¹⁰² auditory dysfunction,^88,102 and ocular irritation.^88,102,128 Chronic exposure to kerosene has also been shown to cause CNS symptoms, including nervousness, loss of appetite, and nausea,¹²⁸ although, like the jet fuels literature, studies on kerosene exposure did not provide context for long-term health impacts or changes in effects that persist long after exposure had ceased. The kerosene literature did not report on the memory impairment, long-term motor deficits, neurologic pain, vestibular function, or measures of neurologic or cognitive and behavioral impairment that were reported in the jet fuels literature. However, there was concordance showing the impacts of both kerosene and jet fuel exposure on neurologic functioning and cognition (ie, CNS symptoms, irritability, anxiety, sensory dysfunction). Therefore, the kerosene literature supported the conclusion that there was slight evidence indicating jet fuel exposure adversely impacts neurologic, cognitive, and behavioral health.

From a clinical perspective, adverse effects on the nervous system have long been observed in patients with exposure to petrochemical substances, such as jet fuels, further supporting these conclusions.¹⁰² Case reports and case series of military personnel document clinical presentation of hearing loss,^61,129 disruption of vestibular function,¹⁰³ eye irritation,^61,83–85 symptoms of intoxication,^102,130 neurological pain or discomfort,^84,85 headache,^61,85 dizziness and fatigue,^61,83 loss of consciousness,¹⁰⁸ disorientation,¹⁰⁸ memory impairment,⁶¹ motor impairment,⁹⁶ racing thoughts,⁸⁴ and depression.⁶¹ Those symptoms were reported mostly after short-term intense exposures such as accidental spills or vapor releases in confined spaces.

Veterans that have been seen at the War Related Illness and Injury Study Center (WRIISC) in New Jersey typically have reported daily low-level jet fuel exposures over long periods of time (usually months to years) via both pulmonary and dermal routes. In addition to chronic symptoms that may have manifested as respiratory issues (ie, cough, difficulty breathing) and/or skin irritation (ie, drying/peeling of the skin, rash), significant neurobehavioral changes have also been noted. Similar to the epidemiologic evidence in the current review, exposed veterans seen in this setting presented with a range of signs and symptoms, such as fatigue, irritability, depression, or anxiety. With chronic exposure occurring over the course of years, some veterans developed chronic encephalopathy with memory deficits and attention impairment, peripheral nervous system dysfunction with autonomic system dysregulation, neurotoxicity with sensorimotor deficits, and, in some cases, neuropathy. Of note, most veterans seen at the WRIISC as of January 2025 reported some degree of hearing impairment (with and without audiometric changes), including tinnitus and hearing loss. However, because loud noise exposure is ubiquitous in military service, it has been difficult to determine the contribution of jet fuel exposure to effects on hearing.

Animal Toxicological Data Summary and Synthesis

There was moderate animal toxicological evidence indicating a negative impact of jet fuel exposure on neurologic health.^20,21 This conclusion was based on consistent evidence of an association supported by at least one high and medium confidence study that did not reach the degree of certainty needed for a robust rating. Of note, associations between jet fuel exposure and neurological outcomes were established by adverse effects on neurotransmitter levels, auditory function, electrophysiological and neurobehavioral outcomes, brain weight, and histopathological endpoints (Table 1 and Supplemental Digital Content, Supplementary Table S9, http://links.lww.com/JOM/C285).

Exposure-induced changes in neurotransmitters can lead to neurotoxicity. All studies assessing neurotransmitter levels in experimental animals following jet fuel exposure observed significant modification to levels of dopamine (or its metabolite DOPAC) and/or serotonin (or its metabolite 5-HIAA).^50,75,76,97 These observations were generally regionally specific, occurring in the hippocampus, cerebral cortex, cerebellum, and brainstem, and modifications were generally observed after a recovery period of 21 to 180 days.

Reports that assessed auditory function and ototoxicity in animals used study designs that mimic occupational exposures of both jet fuel and noise, assessing both independently and together after epidemiologic studies indicated a synergistic amplification of effect (Supplemental Digital Content, Supplementary Table S9, http://links.lww.com/JOM/C285). Most of the studies assessed DPOAE levels, with noise co-exposure levels at a nondamaging 85 dB.^45,67,69,131 Several studies indicated that JP-8 exposure resulted in impaired DPOAE amplitude persisting up to 4 weeks after exposure, suggesting potential permanent alterations.^45,65 Assessment of jet fuel exposure alone generally did not induce DPOAE ototoxicity, although adverse effects were found in studies that assessed levels substantially higher than the DoD permissible exposure level (PEL) of 350 mg/m³.^45,65,66

Rohan et al observed a significant effect on neuron field responses in the hippocampus elicited by several different jet fuel exposures.⁹³ Persistent, multidirectional changes in neurotransmitter levels were observed across different regions of the brain, aligning with the auditory function, electrophysiological, and mechanistic results. These findings further suggest that jet fuel exposure modifies neurotransmitter signaling, possibly resulting in altered neural circuitry.

Most of the studies (7/9) that assessed motor activity and/or coordination observed altered levels of activity in animals, with mixed effects on the directionality of response after jet fuel exposure (Supplemental Digital Content, Supplementary Table S5, http://links.lww.com/JOM/C281, and Supplementary Table S9, http://links.lww.com/JOM/C285). These studies observed both increases^{33,52,54,94,97} and decreases^33,44,50 in ambulation and/or rearing behaviors. In half of the reports assessing both males and females, only female animals exhibited an increase in activity, indicating potential sex-dependent differences.^52,54 Several studies assessing FOB observed modification to spontaneous activity identified as an increase in rearing activity,^52,54,94,97 which is a marker of exploratory nature.⁴⁴ Effects on the autonomic nervous system were also commonly reported, manifesting as increased urination and defecation during open-field testing.^52,54,97 Measurements of muscle tone were not affected by jet fuel exposure; however, one study did identify an increase in grip strength after exposure while also noting that this effect was lost once their apparatuses were serviced part-way through their assessment.⁷⁶ The available animal evidence indicated that jet fuel exposure did not affect social and emotional endpoints; however, few papers assessed these outcomes.^44,76

Dopaminergic-related assays that assessed stimulus sensitization in animals indicated that animals exposed to jet fuels were more likely to pursue a food reward.^50,76 These data correlate to increases in dopamine concentrations in exposed animals. However, only two studies assessed this endpoint after relatively long recovery periods, limiting the interpretation of this finding.

Assessments of animals undergoing operant conditioning tasks, MWM, and passive avoidance testing observed that jet fuel exposure may result in decrements in cognition. Animals exposed to the highest dose of JP-8 (1000 mg/m³) consistently exhibited deficits on operant conditioning tasks of moderate or greater difficulty.⁷⁵ Animals also exhibited increased latency in time to reach the platform and increased swimming distance in the MWM test following exposure to a similar dose of FT, but not JP-8.⁹³ Together, these findings indicate that higher-order cognition, spatial learning, and memory may be differentially affected by high exposure to jet fuels, and it is possible that effects may differ based on fuel type and cognitive domain. Few studies assessed passive avoidance in rats⁷⁶ and field behaviors in dogs⁴⁶; however, no exposure-related effects were noted.

Organ weight may be an important indicator of toxicity in certain body systems. Three high or medium confidence studies observed an increase in absolute and/or relative brain weight (Supplemental Digital Content, Supplementary Table S8, http://links.lww.com/JOM/C284). In two of these studies, however, the authors noted that the increases in relative brain weight could be due to decreases in body weight.^118,119

Histopathological assessment of the CNS assessed in mice and rats observed sporadic increases in nonneoplastic lesions of calcification and mineralization (Supplemental Digital Content, Supplementary Table S8, http://links.lww.com/JOM/C284). Notably, one study observed a significant increase in vascular encephalopathy in females after a year-long recovery period.⁴⁰ Chronic jet fuel exposure was associated with adverse effects, such as cataracts and keratitis,⁴⁰ whereas subchronic or short-term jet fuel exposure did not significantly increase the occurrence of lesions.^{44,52,54–56,90} Subchronic jet fuel exposure effects on the Harderian gland were dependent on jet fuel type and involved mild inflammation.⁵² No adverse effects from jet fuel exposure were observed in the lacrimal or tarsal glands.^{44,54–56,91} The authors suggested that these findings indicate that inhalational exposure to jet fuels may produce mild eye irritation that increases the prevalence of eye crust.^52,54 There were no exposure-related histopathological changes observed in studies that assessed the PNS, including the sciatic nerve.^{40,44,50,54–56,90,91} However, interpretation of the significance of these findings is limited by the lack of quantitative reporting in many studies, as well as inconsistencies in the jet fuels and exposure paradigms.

Mechanistic Data Summary

Mechanistic evidence supported the animal toxicological study findings that jet fuel exposure alters neurotransmitter levels. Mechanistic evidence from cell viability assays and animal toxicological studies demonstrated cell death in auditory cell lines⁷² and rodent ear outer hair cells,^45,65 respectively, suggesting coherence of findings with the observation of ototoxicity in epidemiologic and animal toxicological studies. Both cell death and oxidative stress appeared to differentially impact specific regions of the brain and sensory organ cells, suggesting that whole organ analysis does not provide the necessary granularity to assess specific mechanisms of action following jet fuel exposure.^72,78 Although one study observed alterations in miRNA expression in the brains of rats exposed to jet fuels,⁹⁸ it is unclear whether jet fuel–induced miRNA expression changes are biologically meaningful. Overall, the mechanistic data support the functional neurological endpoints related to alterations in neurotransmitter levels and ototoxicity but are limited by the number of studies available and variability in study/exposure design.

Evidence Integration

Overall, considering the available evidence from human, animal, and mechanistic studies, evidence indicates that exposure to jet fuels is likely to cause neurotoxicity in humans under relevant exposure circumstances (Table 1 and Supplemental Digital Content, Supplementary Table S9, http://links.lww.com/JOM/C285). This conclusion is based primarily on evidence of hearing impairment or abnormal auditory processing in both epidemiologic and animal toxicological studies. Alterations in neurotransmitter levels in exposed animals were consistent with neurobehavioral effects in animals (eg, behavioral sensitization, spontaneous locomotor activity, sensorimotor gating, and auditory processing) and audiological effects identified in both humans and animals. The conclusion is supported by coherent epidemiologic evidence for biologically related effects (eg, memory impairment; ocular conditions; decrements in attention, cognitive function, visual-spatial performance, social-emotional behavior and regulation, and depression). The available mechanistic information provided support for the biological plausibility of the phenotypic effects observed in exposed animals, as well as the activation of relevant molecular and cellular pathways across human and animal models in support of the human relevance of the animal findings. Uncertainty remains given the limited number of quality epidemiologic studies examining neurologic health outcomes, inconsistent direction of effects across types of jet fuels or study designs in animal toxicological studies, and the complexity of associating neurologic effects across multiple jet fuel types.

Effects by Duration of Exposure

The risk of health effects by duration of exposure was only assessed in a small number of primary epidemiologic studies.^{14,26,30,58,80,92,101,132,133} Some studies conducted analyses that considered proxy exposures, such as years of service or employment duration among exposed and unexposed groups. However, these studies did not analyze the impact of employment duration differences explicitly.

Some epidemiologic studies conducted analyses of changes in neurological and behavioral function at exposure intervals that may reflect cumulative exposure over time. For instance, Maule et al observed mixed findings by analyzing changes in balance testing pre- and postshift.¹⁰¹ However, these approaches may be complicated by different exposure pathways. For example, this approach may be useful for long-term inhalation exposures, but employment duration may be a less accurate representation for dermal exposures, which were noted in one study to not be well correlated with employment duration because of intermittent exposure over many years of service.¹³⁴ Duration of jet fuel exposure is a key consideration in persistent hearing loss for groups also exposed to loud noise.⁵⁸ Kaufman et al⁵⁸ examined the differential effects of jet fuel and/or noise exposures on persistent hearing loss by applying different exposure conditions using statistical models. The risk of persistent hearing loss remained statistically significant with an equal increase in exposure to jet fuel and noise exposure duration. Longer durations of jet fuel exposure were also shown to correspond with an increased risk for hearing loss, from “70% at 3 years exposure to 140% at 12 years.”⁵⁸

Animal toxicological studies evaluated durations ranging from hours to greater than 90 days of jet fuel exposure. Most adverse neurologic effects reported in these studies occurred after short-term (1 to 29 days) or subchronic (30 to 90 days) jet fuel exposure (Fig. 5). Ototoxic and motor activity effects were observed almost immediately following exposure to jet fuels, whereas adverse effects on brain weight, neurotransmitter levels, and behavior emerged after short-term or subchronic exposure. Histopathological changes were only apparent after extended subchronic and chronic exposure durations.

FIGURE 5.

Neurologic effects in animal toxicological studies by duration of jet fuel exposure. This heatmap illustrates critical data gaps and the current understanding of the link between exposure duration and exposure effects. Study designs defined by exposure duration categories are represented on the X axis, and different neurological health outcome categories are shown on the Y axis. Within each cell, the number of studies that observed an adverse effect for an endpoint out of the total number of studies that examined that particular endpoint is indicated at each exposure duration, with shading corresponding to the proportion of studies that reported effects of jet fuels. Empty boxes indicate that no studies examined an endpoint for a given duration of exposure. Persistence of effects is reflected in the recovery period column, which shows the number of studies that assessed endpoints after postexposure recovery periods lasting from 1 to 180 days. Data gaps are indicated by the dotted lines. Animal toxicological studies had exposure durations ranging from less than 1 day to greater than 90 days of jet fuel exposure; however, findings primarily characterized short-term and subchronic exposure effects, with relatively little data available on acute and chronic exposures. Most adverse neurologic effects reported in the animal toxicological studies occurred after short-term (1 to 29 days) or subchronic (30 to 90 days) jet fuel exposure. Ototoxicity and motor activity effects were the most immediate following exposure to jet fuel, with adverse effects on brain weight, neurotransmitter levels, and behavior emerging after short-term or subchronic exposure. Histopathological changes were only apparent after extended subchronic and chronic exposure durations.

Data Gaps and Limitations

Uncertainty remains given the limited number of quality epidemiologic studies examining neurologic health outcomes, inconsistent direction of effects across types of jet fuels or study design in animal toxicological studies, and the complexity of evaluating neurologic effects following exposures to the large variety of jet fuel types studied. The epidemiologic research on neurologic, cognitive, and behavioral health outcomes associated with jet fuel exposure lacks high-quality studies. However, the animal toxicological data provide significant evidence for a relationship between jet fuel exposure and neurologic outcomes, with 32 studies reviewed.

The epidemiologic evidence has additional limitations. Several studies did not conduct statistical comparisons. Most studies also categorized exposure groups based on job title or dichotomous exposure status without measuring jet fuel exposure levels in each group. Analysis of long-term health outcomes (ie, months or years after exposure occurred) was limited, with most studies assessing health outcomes among participants actively working and exposed to jet fuels. Concurrent exposure and outcome assessment was common, which limits the ability to make causal inferences on long-term health outcomes following jet fuel exposure. Included case studies and case series did not indicate long-term, irreversible damage, and symptoms were reported to resolve following treatment or removal of exposure. Therefore, there is limited understanding of the persistence of jet fuel-related health outcomes following cessation of exposure and the development of effects with longer latencies.

Results from the reviewed epidemiologic studies may not be generalizable to the broader veteran population. Data describing outcomes in female service members and workers were sparse. Studies in this evidence base frequently did not report potential important characteristics that might be associated with exposures and health outcomes, such as race/ethnicity, lifestyle factors (eg, diet, alcohol consumption), and comorbidities. Most subjects in the available epidemiologic studies included active workers or service members, which were likely healthier than the general population; this may have limited the ability to detect true associations. Further, it is possible that the observational occupational studies were also impacted by healthy worker survivor bias, where previously exposed workers may not have been included in the study population because they may have changed jobs due to health outcomes, retired, or died before the study was conducted.

Drinking water contamination crises have been reported at some military bases; however, understanding the long-term effects resulting from these types of events remains a challenge. For example, some studies have attempted to evaluate health effects related to jet fuel–contaminated water at JBPHH, but these studies have focused on potential acute effects without providing insight into long-term outcomes.^{59,81,105,107} Additional surveillance of this and other impacted communities is necessary to better understand the chronic, neurotoxic consequences of environmental jet fuel exposures.

The effects of various types of jet fuels could not be assessed given the limited available epidemiologic and animal toxicological evidence on specific fuel types. Exposed workers and personnel from epidemiologic studies included in this review were predominantly exposed to JP-8. Some studies did not report the type of jet fuel to which individuals were exposed (n = 9). In addition, no studies included in this review conducted thorough exposure assessments to identify whether co-exposures to other potentially neurotoxic hazards, such as industrial solvents, could have occurred. For animal toxicological studies, although there were more data of higher quality available, few endpoints (ie, auditory function and ototoxicity) were investigated for the same type of jet fuel across the various studies. Additionally, the doses and exposure paradigms used in the animal studies to identify hazards associated with jet fuel exposure may not be relevant to expected human exposure scenarios, limiting the ability to draw conclusions about effects in humans where only data in animals are available. Most of the animal toxicological studies utilized a variety of jet fuel types and exposure paradigms; therefore, it is difficult to draw definitive conclusions when there was an inconsistent direction of effects across jet fuel type and study design. Collectively, it was not possible to differentiate the effects of specific jet fuels given the available body of evidence.

In general, evidence from animal studies suggests that exposure to various jet fuels can result in persistent, adverse effects across different neurologic outcomes. Studies consistently noted changes in neurotransmitter levels that may translate into functional and behavioral alterations.^67,68,75 If feasible, future epidemiologic studies should prioritize the assessment of neurobehavioral outcomes known to be modulated by those brain regions adversely impacted in experimental investigations. For example, neurochemical changes found within the limbic system and cerebral cortex may align with cognitive deficits and social and emotional effects observed in both humans and animals. Epidemiologic studies focused on the identification of neurobehavioral outcomes that have measurable brain region- or circuit-specific correlates would increase clinical precision for the detection and targeted treatment of jet fuel-related neurologic and behavioral health outcomes.

The animal toxicological and mechanistic data demonstrate that auditory processing is particularly vulnerable to the effects of jet fuels. Exposure to jet fuels and a subototoxic level of noise resulted in long-term CAPD and neurotransmitter alterations that persisted long after exposure ended.^50,67,68,75 Further, changes in the expression of genes linked to neurotransmitter secretion and receptor binding in rats, as well as in vitro evidence of jet fuel cytotoxicity, provide additional support for the observed adverse auditory outcomes.^71,72,77 These data should inform future research in human populations, as it is vital to underscore that CAPD, which entails neurophysiologic alterations that distort the perception of sensory information, was induced in the absence of detectable sensory cell damage or functional hearing loss in animals. This finding implies that CAPD would go undetected in typical audiometric assessments of hearing function in humans. Beyond various audiologic deficits, the adverse implications for CAPD extend to cognition, as CAPD corresponds to degraded neural signals to the cortex that compete for cognitive resources, contributing to impairments in attention, memory, and visuomotor task performance.^67,68 Therefore, it is critical that future epidemiologic studies focus on increasing the understanding of how jet fuel exposures impact central auditory processing and auditory brainstem circuitry.

In summary, several factors limit the ability to draw stronger conclusions based on the available epidemiologic, animal toxicological, and mechanistic evidence. The body of literature lacks prospective cohort studies with reliable exposure assessment and sufficient follow-up time to collect data on health outcomes with long latency periods or that tend to develop later in life. Additional studies in humans are needed to confirm observed associations and to achieve consistency, specificity, temporality, biological gradient, plausibility, and coherence of the associations and, ultimately, to increase the ability to make causal determinations.^16,19

The results from the current review indicate that exposure to jet fuels is likely to cause neurotoxicity in humans under relevant exposure circumstances (Table 1 and Supplemental Digital Content, Supplementary Table S9, http://links.lww.com/JOM/C285). This conclusion was based primarily on evidence of hearing impairment or abnormal auditory processing in both epidemiologic and animal toxicological studies. Alterations in neurotransmitter levels in exposed animals were consistent with neurobehavioral effects (eg, behavioral sensitization, spontaneous locomotor activity, sensorimotor gating, and auditory processing) and audiological effects identified in both humans and animals. The conclusion was supported by coherent epidemiologic evidence for biologically related effects (eg, memory impairment, ocular conditions, decrements in attention, cognitive function, and visuospatial performance, as well as increases in depression and anxiety and other social and emotional behavior and regulation symptoms). The available mechanistic information provided support for the biological plausibility of the phenotypic effects observed in exposed animals, as well as the activation of relevant molecular and cellular pathways across human and animal models. Finally, the determination that evidence indicates that exposure to jet fuels leads to neurologic, cognitive, and behavioral outcomes is consistent with the 2003 NRC toxicological assessment that concluded that JP-8 was potentially toxic to the nervous system based on animal data that were available at that time.¹⁷

Taken together, the current body of evidence supports a relationship between jet fuel exposure and neurologic as well as cognitive and behavioral effects. Even with the noted limitations, data are consistent enough across data streams to allow researchers to determine that there are established effects on sensory functions, motor coordination, memory, attention deficits, and depressive symptoms. These relationships are further supported by available mechanistic data that highlight neurotoxic changes in the brain, sensory organs, and associated neural circuitry. Notably, a strength of the current review was that it included a methodology that emphasized examination of both acute and chronic outcomes to ensure a more detailed evaluation of health risks, as well as inclusion of mechanistic data, allowing for the ability to draw conclusions even when human and/or animal data were lacking.²² Additional studies are needed to better understand the long-term effects of jet fuel exposures on the health of impacted populations, such as those who served in the military.