Jet Fuel Effects on Hepatic and Renal Health

Abstract

Objective

The aim of this study was to assess the possible hepatic and renal health effects of jet fuels used by the US military.

Methods

A systematic literature review utilizing epidemiologic, animal toxicological, and mechanistic studies was conducted to evaluate hepatic and renal health effects following jet fuel exposure.

Results

Epidemiologic evidence for renal and hepatic outcomes was indeterminate, primarily due to the limited number and quality of human studies. Animal toxicological studies provided moderate evidence that jet fuel exposure impacts the renal system, while there was slight evidence for hepatic effects.

Conclusions

Evidence suggests that exposure to jet fuels may cause nephrotoxicity and hepatotoxicity in humans. However, uncertainty remains due to the inconsistent direction of effects, the limited number of studies examining specific health outcomes, and the few published human studies available for review.

LEARNING OUTCOMES

Upon reviewing this manuscript, readers will be able to:

• Interpret the state of the available scientific literature regarding the effects of jet fuel exposure on the hepatic and renal systems

• Summarize the possible hepatic and renal health effects associated with jet fuel exposure supported by epidemiologic, animal toxicological, and mechanistic evidence

• Describe data gaps and challenges that present an opportunity for future research to better understand the long-term hepatic and renal effects of jet fuel exposure.

Jet fuel is a common exposure among service members.^1,2 Military personnel (service members and the civilian industrial base) may be at risk of jet fuel exposure while performing routine tasks, such as fueling aircraft, maintenance and performance testing of military vehicles, and storing and transporting jet fuels.^3–5 Exposure can occur through inhalation, accidental ingestion, and dermal contact.^6,7 In addition to occupational exposures, environmental exposures can also occur as a result of spills or leaks, such as the water contamination events that occurred at Marine Corp Base Camp Lejeune⁸ between the 1950s and 1980s and the Red Hill Bulk Fuel Storage Facility⁹ in 2021.

Although many authoritative sources, such as the Agency for Toxic Substances and Disease Registry^6,7 and the International Agency for Research on Cancer,¹⁰ have previously evaluated the health risks of jet fuel exposure, the possible long-term health effects in humans are currently not well understood. These reviews generally did not find any epidemiological studies. However, evidence in animals suggests that continued exposure to fuel oils, including kerosene (a major component of jet fuel), has the potential to cause kidney damage (e.g., nephropathy and increased kidney weights) and effects in the liver (e.g., hepatic inflammation and fatty change).¹¹ It is important to determine whether this evidence correlates with potential consequences that service members and veterans may sustain as a result of their service.

Considering the importance of renal and hepatic systems in detoxification, there are concerns about potential harm from exposure to toxic substances like jet fuels. To better understand the state of the science, data gaps, and limitations regarding the possible health effects of jet fuel exposure, the US Department of Veterans Affairs conducted a systematic literature review of the available epidemiologic evidence (military and occupational exposure-related data) in 2024.^12,13 The US Department of Veterans Affairs' review of the occupational literature did not indicate changes in the hepatic or renal systems after jet fuel exposure but was limited by the quality and quantity of available evidence. The current review aimed to further evaluate the relevant epidemiologic literature (including occupational and environmental exposures) and incorporate the available animal toxicological and mechanistic evidence to improve the understanding of hepatic and renal effects associated with exposure to jet fuels. This work is part of a larger systematic review¹⁴ that covers a wide range of health effects and analyses of possible cancer, neurologic, cardiovascular and hematological, respiratory, immune, renal and hepatic, and endocrine and reproductive effects.

METHODS

The methodology utilized for this fit-for-purpose systematic literature review was adapted from the Integrated Risk Information System (IRIS) Handbook used by the US Environmental Protection Agency (EPA).^15,16 The review was designed to capture epidemiologic, animal toxicological, and mechanistic literature on the health impacts of jet fuel exposure. The review also considered the effect of exposure duration on health outcomes and the link between immediate (acute) health outcomes and long-term health outcomes. 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 the kidneys and liver in humans. A more detailed description of these methods can be found in Bergeron et al. (2025).¹⁴

Literature Search Strategy

The Populations, Exposures, Comparators, and Outcomes (PECO) criteria guided the development of the literature search strategy to identify epidemiologic, animal toxicological, and mechanistic references. Literature searches for relevant epidemiologic, animal toxicological, and mechanistic evidence were conducted in March 2025. The literature searches were carried out in four distinct types of sources to guarantee a comprehensive body of literature: (1) scientific literature databases (PubMed and EBSCOhost), (2) gray literature or publications produced outside of traditional scientific publishing avenues, (3) expert-identified publications and reports, and (4) references cited in identified secondary reviews.

Inclusion and Exclusion Criteria

The literature search and screening procedures, including the inclusion and exclusion of studies, are guided by the PECO criteria. In brief, the review focused on humans, vertebrates, or in vitro models (population) exposed to jet fuels (exposure) compared with control groups of low or no exposure (comparator) reporting hepatic and/or renal health effects (outcome). Supplemental material for this review included case studies, case reports, case series, and/or secondary data sources (such as literature reviews) but was not considered when determining the weight of the evidence or as part of the synthesis of the evidence.

Literature Screening and Data Extraction

The PECO relevancy of all references was determined during title/abstract and full-text screening. Two independent reviewers evaluated all references with conflicts resolved by a subject matter expert. Only references that were PECO-relevant progressed to full-text screening. Studies deemed not PECO-relevant during screening did not proceed to study quality evaluation or data extraction. Overlapping or partially overlapping data sets, identified as multiple references reporting results from the same epidemiologic or animal toxicological study population, were identified during the screening process. To increase transparency on the number of unique references during the reporting process, overlapping data sets were not considered independently during evidence synthesis. However, those with partially overlapping data sets were included, because they reported on different endpoints.

Data extraction was performed on all PECO-relevant primary epidemiologic, animal toxicological, and mechanistic studies to identify and compile study details and results. Extraction was conducted by primary extractors with accuracy confirmed by a secondary reviewer. Data were extracted for all health outcome endpoints, regardless of study quality. Only qualitative data were extracted from case reports, case studies, case series, secondary reviews, and mechanistic studies.

Study Quality Evaluation

For each endpoint in a PECO-relevant study, trained evaluators assessed study quality followed by a second senior evaluator and any disagreements were brought to a subject matter expert for discussion. This approach was a deviation from EPA's IRIS Handbook for efficiency. Evaluators 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 for each study quality domain. The overall study confidence (high, medium, low, or uninformative) was then determined.¹⁵ To the greatest extent feasible, the overall confidence rating represents assessments of the prospective impact on the outcomes, considering the strength and/or direction of that impact in each domain. Since study quality was assessed for each endpoint in a study, multiple judgments may exist for a domain or overall confidence rating based on differences by endpoints. Study quality evaluation was not conducted for mechanistic studies, secondary reviews, case reports, case studies, or case series and was only conducted on one of the studies when overlapping data sets were identified. The rationales for the study quality ratings can be found on Tableau, a free public platform, within the study quality evaluation heatmap: https://public.tableau.com/app/profile/vha.home/viz/SupportingInformationforVHAJetFuelsReport_17002413903760/ReadMe?publish=yes.

Evidence Synthesis and Integration

During evidence synthesis, the overall study confidence was considered for epidemiologic and animal toxicological studies. High- and medium-confidence studies were prioritized over low-confidence studies and uninformative studies. Uninformative epidemiologic studies were considered in the evidence synthesis due to the limited available literature, while uninformative animal toxicological studies were not included in the evidence synthesis. Separate final judgment calls (i.e., robust, moderate, slight, indeterminate, and compelling evidence of no effect) were assigned to the overall body of epidemiologic and animal toxicological evidence based on the quantity and quality of the available studies as detailed within the IRIS Handbook,¹⁵ which modulated Hill's¹⁷ causality criteria.

Evidence integration judgments were developed through a comprehensive review of the data with consideration of several factors, such as the relevance of animal toxicological findings to human health, consistency within and across evidence streams, sensitivity to susceptible populations, and biological plausibility and mode of action. Mechanistic evidence was included in the synthesis and evidence integration to increase understanding of the biological plausibility of human health outcomes. Overall judgments consider the epidemiologic, animal toxicological, and mechanistic evidence and include evidence demonstrates, evidence indicates (likely), evidence suggests, evidence inadequate, and strong evidence supports no effect.¹⁵

RESULTS

An interactive Tableau Dashboard (Seattle, WA) was produced to allow visualization of the scientific evidence from all steps of the systematic literature review process. This dashboard includes a diagram according to the Interactive Reference Flow¹⁸ approach intended to provide transparency and traceability for systematic review results; study quality evaluation heatmaps with justifications for the overall confidence scores for all epidemiologic and animal toxicological studies; and evidence maps for all epidemiologic, animal toxicological, and mechanistic studies. It can be viewed at https://public.tableau.com/app/profile/vha.home/viz/SupportingInformationforVHAJetFuelsReport_17002413903760/ReadMe?publish=yes. The results of the study identification process are presented in Figure 1. The literature search returned a total of 4291 references, and 621 were deemed PECO-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 mechanistic references.

FIGURE 1.

Reference flow diagram of the search, screening, and selection of renal system health outcome studies included in the review. This figure provides an overview of the study identification process results. The literature search yielded 4291 references. After completing title and abstract screening and full-text screening, 279 references were deemed Populations, Exposures, Comparators, and Outcomes (PECO)-relevant, with 42 epidemiologic studies and 125 animal toxicological references. Of the 279 total PECO-relevant references, 74 specifically discussed renal effects of jet fuel exposure, including four epidemiologic references, three case reports or case series, 41 animal toxicological references, eight mechanistic references, and 18 secondary data sources. ^aA study may have reported on multiple model types; therefore, the total for the category was greater than the total PECO-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. Four 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. ^dNine references reported on the same animal toxicological study of renal health outcomes. Four additional references were classified as a partial overlap as they reported on a portion of the same renal endpoints as another reference; however, all other renal endpoints reported were unique. After excluding reports of the same data, there were 32 unique animal toxicological studies in this body of literature.

Renal

Literature Search and Study Selection

A total of 74 references focused on renal health outcomes, including four epidemiologic references, 41 animal toxicological references, and eight mechanistic references (Fig. 1). Of the four primary epidemiologic references assessing the association between jet fuel exposure and renal outcomes, all were considered low confidence (Fig. 2). Concerns identified in the low-confidence references included potential participant selection bias, exposure misclassification due to measurement methods, potential for residual confounding variables, unclear analyses and/or lack of adequate reporting of effect measures, and limited study sensitivity.

FIGURE 2.

Summary of study quality evaluation results for renal outcomes for epidemiologic studies of jet fuel exposure. This heatmap provides an overview of the study quality ratings assigned to the four epidemiologic studies that reported renal effects following jet fuel exposure. The validity and utility of each study was assessed based on potential bias related to participant selection, exposure measurement, outcome ascertainment, potential confounding, analysis, selective reporting, and study sensitivity. The evaluation domain rating (e.g., good, adequate, deficient, critically deficient) and overall study confidence classification (e.g., 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 Handbook¹⁵ and are further discussed in Bergeron et al. (2025).¹⁴ All four studies were considered low confidence.

After accounting for overlapping data sets in the 41 animal toxicological studies that were deemed PECO-relevant, 32 unique studies were identified that assessed the association between jet fuel exposure and renal outcomes. Of these, two were considered high confidence, three were mixed confidence (high/medium), three were medium confidence, two were mixed confidence (medium/low), one was mixed confidence (medium/uninformative), one was mixed confidence (medium/low/uninformative), 17 were low confidence, one was mixed confidence (low/uninformative), and two were uninformative (Fig. 3). Concerns identified in the low-confidence and uninformative studies included reporting deficiencies such as incomplete information about animal allocation to exposure groups, contained confounding variables, high levels of attrition, lack of detail on jet fuel characterization and administration, concern regarding endpoint sensitivity and specificity, and/or lack of detailed results that reduced the ability to interpret findings.

FIGURE 3.

Summary of study quality evaluation results for renal outcomes for animal toxicological studies of jet fuel exposure. This heatmap provides an overview of the study quality ratings assigned to the 32 animal toxicological studies that reported renal effects following jet fuel exposure. The validity and utility of each study was assessed based on potential bias related to reporting; allocation; observational bias and blinding; confounding variables; reporting and attrition; chemical administration and characterization; exposure timing, frequency, and duration; endpoint sensitivity and specificity; and results presentation. The evaluation domain rating (e.g., good, adequate, deficient, critically deficient) and overall study confidence classification (e.g., 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 Handbook¹⁵ and are further discussed in Bergeron et al. (2025).¹⁴ Of the 32 primary animal toxicological studies assessing the association between jet fuel exposure and renal outcomes, two were considered high confidence, three were mixed confidence (high/medium), three were medium confidence, two were mixed confidence (medium/low), one was mixed confidence (medium/uninformative), one was mixed confidence (medium/low/uninformative), 17 were low confidence, one was mixed confidence (low/uninformative), and two were uninformative. ^aBogo et al.¹⁹ (1983) had a partially overlapping data set with Parker et al.²⁰ (1981) for some renal health outcomes; therefore, this paper underwent study quality evaluation for unique respiratory health outcomes only. ^bMacEwen and Vernot (1984, 1983, 1982, 1981, and 1978)^21–25 reported overlapping data sets with Kinkead et al.²⁶ (1995), Kinkead et al.²⁷ (1991), Bruner et al.²⁸ (1993), Mattie et al.²⁹ (1991), Gaworski et al.³⁰ (1985), MacEwen and Vernot³¹ (1985), and Haun et al.³² (1985) for all renal health outcomes; therefore, these papers did not undergo study quality evaluation. ^cMacEwen and Vernot³³ (1980) had a partially overlapping data set with Kinkead et al.²⁶ (1995), Kinkead et al.²⁷ (1991), Bruner et al.²⁸ (1993), Gaworski et al.³⁰ (1985), and Haun et al.³² (1985) for some renal health outcomes; this paper underwent study quality evaluation for unique renal health outcomes only. ^dMacEwen and Vernot³¹ (1985) had a partially overlapping data set with Kinkead et al.²⁶ (1995), Bruner et al.²⁸ (1993), Mattie et al.²⁹ (1991), Gaworski et al.³⁰ (1985), and Haun et al.³² (1985) for some renal health outcomes; therefore, this paper underwent study quality evaluation for unique renal health outcomes only. ^eDodd³⁴ (1996) and Nordholm et al.³⁵ (1999) had an overlapping data set with MacMahon et al.³⁶ (1998) for all renal health outcomes; therefore, these papers did not undergo study quality evaluation. ^fMattie et al.³⁷ (2023) had an overlapping data set with Sterner et al.³⁸ (2015) for all renal health outcomes; therefore, this paper did not undergo study quality evaluation. ^gMattie et al.³⁹ (2020) had an overlapping data set with Sterner et al.⁴⁰ (2015) for all renal health outcomes; therefore, this paper did not undergo study quality evaluation. ^hSterner et al.⁴¹ (2020) had a partially overlapping data set with Wong et al.⁴² (2013) for some renal health outcomes; this paper underwent study quality evaluation for unique renal health outcomes only.

Kidney and Urinary Bladder Histopathology

Histopathological changes in the kidneys were a common observation, with the majority of studies observing an increased incidence and/or severity of non-neoplastic changes in rodents, regardless of jet fuel type, exposure paradigm, or route of exposure (Supplemental Digital Content, Table S1, http://links.lww.com/JOM/C305).^{20,26–30,32,38,40,41,43–48} Common non-neoplastic lesions observed in male rats included mineral deposits/mineralization^{26–30,32,38,40} and hyaline droplet accumulation.^{20,26,29,38,40,41,45–47} Other effects in male rats were less common, such as tubular damage/degeneration,^{30,32,38,40,43,44} hyperplasia,^26–30,32 fibrosis,^38,40 inflammation,^38,40 and necrosis.³⁰ Nephropathy was also a commonly observed non-neoplastic lesion, with the severity of nephropathy increased with jet fuel exposure in four studies.^26,28,29,47 One of these studies further examined the ultrastructure of the kidneys in jet fuels–exposed male rats and described changes such as irregularly shaped mitochondria, crystalloid inclusions in the proximal tubule cells, and necrotic tubular epithelial cells that obstructed the tubules.²⁶

The observed non-neoplastic lesions were more common in male rats than in female rats or other animal models. Three studies in female rats observed increased incidences of non-neoplastic lesions in the kidney, including tubular pigmentation,³² mineralization,³⁸ and periglomerular fibrosis and inflammation.⁴⁰ One study showed decreased incidences of mineralization and nephropathy in female rats.²⁷ In studies involving mouse models, one reported an increased incidence of renal tubule dilation in female mice,²⁶ while another study observed an increased incidence of amyloid in both male and female mice.⁴⁸

However, all other studies in mice observed no effects.^{27,28,30,32,33,49,50} No histopathological changes in the kidneys were also noted in some studies in rats.^{19,33,42,51,52} Furthermore, no effects were observed in fathead minnows,⁵³ hamsters,³² or dogs.^26,30,32,33 Lastly, no effects were observed in urinary bladder histopathology for any animal species.^{19,20,27,28,30,40,42,45,48,49,51}

Kidney Weight

Several studies reported that kidney weights increased following exposure to jet fuels (Supplemental Digital Content, Table S1, http://links.lww.com/JOM/C305).^{26,28,29,31,33,41,42,45–47,51,54} In male rats chronically exposed to jet propellant (JP)-4 via inhalation, significant increases in absolute and relative kidney weights were observed.⁵⁴ In Sterner et al.⁴¹ (2020), significant increases in absolute and/or relative kidney weights were observed in male and female rats after short-term inhalation exposure to hydroprocessed esters and fatty acids-F (HEFA-F). In this study, male rats experienced a significant decrease in absolute kidney weight after an acute exposure, whereas relative kidney weights in female rats were non-significantly decreased. Two studies reported significant increases in relative kidney weights in male and female rats following oral exposure to JP-8; however, absolute kidney weights were not altered, and changes in body weight were not reported.^47,51

Several inhalation studies reported inconsistent effects on absolute and/or relative kidney weights between males and females and/or across time points. Three of these studies reported exposure-related increases in absolute and relative kidney weights of male rats, but not female rats following subchronic inhalation exposure to JP-4,²⁶ HEFA-C,⁴² or JP-8,²⁹ Relative kidney weights of male rats chronically exposed to JP-4 were significantly higher than controls; however, similar to subchronic exposure, no effect was observed in females following a chronic exposure.²⁸ Conversely, in rats exposed to synthetic-8 (S-8), the absolute kidney weights of female rats were elevated, but this effect was not observed in males.^45,46 Several studies with post-exposure periods (6 to 19 months) showed inconsistent changes in kidney weights across time points.^26,30,31 Significant increases in absolute and relative kidney weights occurred only during the exposure period but not in the postexposure periods in two subchronic inhalation studies of JP-4 in several strains of male rats.^26,31 In the third study, both increases and decreases in absolute and relative kidney weights were observed in male and female rats after subchronic inhalation exposure to petroleum and shale JP-5. However, the changes varied by time point and sex, and the authors stated that they were incidental.³⁰

In other studies in rats, kidney weights were not affected following jet fuel exposure via inhalation^{27,36,38,40,52} or gavage.⁵⁵ Studies that examined kidney weight in mice found no effects from exposure to jet fuels, regardless of the exposure scenario or type of jet fuel used.^26,49,56,57 Similarly, no effects were observed in dogs.^26,30,33

Clinical Pathology

Epidemiology

Four primary epidemiologic studies assessed serum and urinary biomarkers of kidney function and reported no significant associations with jet fuel exposure (Supplemental Digital Content, Table S2, http://links.lww.com/JOM/C306).^58–61 Olsen et al.⁵⁹ (1998) observed active-duty and civilian personnel at Hill Air Force Base during the transition of use of JP-4 to JP-8 fuel, and at 3, 6, and 18 months afterward, and reported no change in blood urea nitrogen (BUN) and creatinine (CREA) at any time point. A study of US Air National Guard members observed no difference in urinary appearance, color, bilirubin, glucose, hemoglobin, ketone bodies, or pH in JP-8–exposed versus unexposed subjects.⁶⁰ In addition, one retrospective cohort study of individuals exposed to a JP-5 release at Joint Base Pearl Harbor-Hickam reported no difference in hematuria incidence among exposed versus unexposed participants.⁶¹ One study compared rates of mortality due to any urogenital disease in a cohort of Swedish Armed Forces personnel with the Swedish general population using standardized mortality ratios; however, no urogenital disease mortality was observed in the Armed Forces personnel during the 9-year follow-up period.⁵⁸

Animal Toxicology: Serum Biomarkers

Numerous studies evaluated the impact of jet fuel on serum biomarkers of renal function (Supplemental Digital Content, Table S1, http://links.lww.com/JOM/C305). Four biomarkers, which included BUN, CREA, creatine kinase (CK), and uric acid (UA), were evaluated in the available studies, and several studies reported increases in these biomarkers, generally in male rats. Parker et al.²⁰ (1981) evaluated the effects of acute gavage exposure to JP-5 and its shale-derived products on male rats, and reported increased CREA levels following JP-5, shale A, shale B, and shale C exposure. BUN and CREA levels were increased in male rats only in a chronic inhalation study of JP-7 and JP thermally stable.²⁷ A subchronic, oral gavage study of JP-8 in male rats reported increased CREA levels that were not dose-responsive.⁴⁷ Studies with multiple measurements (during exposure, directly after exposure, and/or during post-exposure periods [2 weeks to 21 months]) also showed increases in BUN and/or CREA, but changes were inconsistent across time points and often between the sexes. These included three subchronic inhalation studies in rats, one of shale and petroleum JP-5,³⁰ one of JP-8,²⁹ and two of JP4.^26,31 One of the studies further showed that there may be strain-specific differences, as changes were inconsistent between the four strains of rats studied.³¹

Other studies generally showed decreases in these biomarkers, particularly in females, but these changes also tended to be inconsistent between sex, time point, and jet fuel type within a study. Bruner et al.²⁸ (1993) reported decreased BUN and CREA levels in female Fischer-344 (F-344) rats after chronic JP-4 exposure. In addition, after short-term Jet-A exposure, Sweeney et al.⁵² (2013) observed decreased BUN levels in female Sprague-Dawley 14 days post-exposure, but not in female F-344 rats, while CREA was unchanged. Another study reported a decrease in CREA in female, but not male, rats following subchronic inhalation of the bio-based jet fuel Gevo alcohol-to-jet synthesized paraffinic kerosene (Gevo ATJ SPK).⁴⁰ Importantly, the authors noted a lack of dose-response in this study and, thus, questioned the toxicological significance of this change. However, after subchronic inhalation exposure to shale JP-4, male rats exhibited significantly decreased BUN levels, while female rats showed decreased CREA levels.³¹ In addition, in an acute gavage study of JP-5 and its shale-derived products in male rats, BUN levels were not changed following JP-5 and Shale B, while they inconsistently decreased following Shale A and Shale C administration.²⁰

Other studies in rats showed no effects on BUN or CREA, including a short-term inhalation study in both petroleum- and shale-derived JP-5,¹⁹ subchronic oral exposure to JP-8,⁵¹ and subchronic inhalation exposures to S-8,⁴⁵ Swedish biofuels 8 (SB-8),³⁸ and HEFA-C.⁴² No changes in BUN or CREA were observed in dogs after an acute exposure to JP-10 or a subchronic exposure to JP-5/aviation gas mixture,³³ after subchronic exposure to JP-4²⁶ and JP-5,³⁰ or after a chronic exposure to JP-10³² (Supplemental Digital Content, Table S1, http://links.lww.com/JOM/C305). No changes were observed in serum CK^{20,38,40–42,45} and UA⁵¹ concentrations after exposure to jet fuels in any of the available studies.

Animal Toxicology: Urinalysis

Several studies evaluated jet fuel effects on urinary endpoints in male and/or female rats, including pH, total volume, specific gravity, protein, and CREA (Supplemental Digital Content, Table S1, http://links.lww.com/JOM/C305). Significant decreases in urinary pH were observed in male and female rats following 10 days of inhalation to HEFA-F, but not after 1- or 5-day exposures,⁴¹ as well as in male rats following subchronic gavage of JP-8.⁴⁷ However, in two subchronic inhalation experiments of JP-4 by the same authors, urinary pH of male rats was inconsistently changed. In one experiment, decreased urinary pH was reported in F-344 male rats, whereas the second experiment showed significantly increased urinary pH in all four strains evaluated (F-344, Sprague Dawley, Wistar, and Osborne Mendel).³¹ Inconsistent changes were also reported for urine osmolality. Two studies reported significantly decreased urine osmolality in F-344 male rats following subchronic inhalation exposure to JP-4³¹ and JP-8.²⁹ However, in the second experiment in the JP-4 study, significant increases in osmolality were observed in F-344, Sprague Dawley, and Osborne-Mendel strains but not Wistar rats. In Sterner et al.⁴¹ (2020), small concentrations of ketones, leukocytes, and blood were detected in male rats exposed to HEFA-F for 10 days but were not observed in the females or males exposed to HEFA-F for 1 or 5 days.

Other studies reported no changes in urinary parameters. No effects on urinary pH were observed following 90-day exposure in female rats.⁵¹ In addition, no significant effects on urine protein, CREA, total volume, specific gravity, urobilinogen, glucose, bilirubin, nitrite, and/or epithelial cell number were reported in male and/or female rats following jet fuel exposure.^41,47,51

Mechanistic Data

Eight studies evaluated how jet fuel exposure impacts renal outcomes in rodents using mechanistic endpoints (Supplemental Digital Content, Table S3, http://links.lww.com/JOM/C307). Of these eight studies, four studies evaluated the effects of JP-8 exposure.^43,44,62,63 The other four studies evaluated either HEFA-C,⁴² S-8,⁴⁵ SB-8,³⁸ or Gevo ATJ SPK jet fuels.⁴⁰

Five of the studies evaluated the effects of jet fuel exposures on α_2u-globulin, a protein that is expressed primarily in male rats and that can accumulate and lead to cytotoxicity, whereby injured cells are released into the tubule lumen. Four of the studies that examined α_2u-globulin levels in male and female rat kidney tissue in response to jet fuel inhalation found significantly elevated levels in males.^38,40,42,44 However, one study that measured this protein in male and female rat kidney tissue following S-8 synthetic jet fuel inhalation showed no significant changes.⁴⁵

Four of the studies evaluated changes in protein expression in kidney tissue following inhalation exposure to JP-8. Specifically, two of the studies evaluated JP-8 exposure in male rats for the expression of heat shock protein-70 (HSP70), which is largely involved in maintaining protein homeostasis and proper protein folding; this protein is upregulated in response to stress stimuli, including oxidative stress.^43,44 Both studies observed increases in HSP70 in response to JP-8, although only the changes reported in Larabee et al⁴³ (2005) reached statistical significance. Global protein expression changes in kidney tissue were evaluated in two studies exposing either male rats⁶² or male mice⁶³ to JP-8. Witzmann et al⁶² (2000) observed upregulation of glutathione S-transferase, which is involved in the detoxification of xenobiotics, and 10-formyltetrahydrofolate dehydrogenase, which is involved in catalyzing NADP⁺ (nicotinamide adenine dinucleotide phosphate)-dependent oxidation. In a separate study, Witzmann et al⁶³ (2000) reported differential expression of proteins involved in vesicular machinery, metabolic stress, detoxification systems, intracellular ultrastructure, and acid-base homeostasis and fluid secretion following JP-8 exposure.

Hepatic

Literature Search and Study Selection

The results of the study identification process are provided in Figure 4. A total of 74 references examined hepatic health outcomes, including three epidemiologic references, 43 animal toxicological references, and nine mechanistic references. All three of the primary epidemiologic references assessing the association between jet fuel exposure and hepatic outcomes were considered low confidence (Fig. 5). Concerns identified in these low-confidence studies included participant selection bias, exposure misclassification due to measurement methods, potential for residual confounding variables, unclear analyses and/or lack of adequate reporting of effect measures, and limited study sensitivity.

FIGURE 4.

Reference flow diagram of the search, screening, and selection of hepatic system health outcome studies included in the review. This figure provides an overview of the study identification process results. The literature search yielded 4291 references. After completing title and abstract screening and full-text screening, 279 references were deemed Populations, Exposures, Comparators, and Outcomes (PECO)-relevant, with 42 epidemiologic studies and 125 animal toxicological references. Of the 279 total PECO-relevant references, 74 specifically discussed hepatic effects of jet fuel exposure, including three epidemiologic references, 43 animal toxicological references, nine mechanistic references, and 19 secondary data sources. ^aA study may have reported on multiple model types; therefore, the total for the category was greater than the total PECO-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. Four 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. ^dNine references reported on the same animal toxicological study of hepatic health outcomes. Four additional references were classified as a partial overlap as they reported on a portion of the same hepatic endpoints as another reference; however, all other hepatic endpoints reported were unique. After excluding reports of the same data, there were 34 unique animal toxicological studies in this body of literature.

FIGURE 5.

Summary of study quality evaluation results for hepatic outcomes for epidemiologic studies of jet fuel exposure. This heatmap provides an overview of the study quality ratings assigned to the three epidemiologic studies that reported hepatic effects following jet fuel exposure. The validity and utility of each study was assessed based on potential bias related to participant selection, exposure measurement, outcome ascertainment, potential confounding, analysis, selective reporting, and study sensitivity. The evaluation domain rating (e.g., good, adequate, deficient, critically deficient) and overall study confidence classification (e.g., 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 Handbook¹⁵ and are further discussed in Bergeron et al¹⁴ (2025). All three studies were considered low confidence.

After accounting for overlapping data sets in the 43 animal toxicological studies assessing the association between jet fuel exposure and hepatic outcomes, 34 unique studies were identified. Of these, two were considered high confidence, three were mixed confidence (high/medium), four were medium confidence, two were mixed confidence (medium/low), one was mixed confidence (medium/low/uninformative), one was mixed confidence (medium/uninformative), 17 were low confidence, one was mixed confidence (low/uninformative), and three were uninformative (Fig. 6). Concerns identified in these low-confidence and uninformative studies included reporting deficiencies such as 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, concern regarding endpoint sensitivity and specificity, and/or lack of detailed results that reduced the ability to interpret findings. The uninformative animal studies were excluded from further analysis and were not included in the synthesis.^64–66

FIGURE 6.

Summary of study quality evaluation results for hepatic outcomes for animal toxicological studies of jet fuel exposure. This heatmap provides an overview of the study quality ratings assigned to the 34 animal toxicological studies that reported hepatic effects following jet fuel exposure. The validity and utility of each study was assessed based on potential bias related to reporting; allocation; observational bias and blinding; confounding variables; reporting and attrition; chemical administration and characterization; exposure timing, frequency, and duration; endpoint sensitivity and specificity; and results presentation. The evaluation domain rating (e.g., good, adequate, deficient, critically deficient) and overall study confidence classification (e.g., 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 Handbook¹⁵ and are further discussed in Bergeron et al¹⁴ (2025). Of the 30 primary animal toxicological studies assessing the association between jet fuel exposure and hepatic outcomes, two were considered high confidence, three were mixed confidence (high/medium), four were medium confidence, two were mixed confidence (medium/low), one was mixed confidence (medium/low/uninformative), one was mixed confidence (medium/uninformative), 17 were low confidence, one was mixed confidence (low/uninformative), and three were uninformative. ^aBogo et al¹⁹ (1983) had a partially overlapping data set with Parker et al²⁰ (1981) for some hepatic health outcomes; therefore, this paper underwent study quality evaluation for unique respiratory health outcomes only. ^bMacEwen and Vernot (1984, 1983, 1982, 1981, and 1978)^21–25 reported overlapping data sets with Kinkead et al²⁶ (1995), Kinkead et al²⁷ (1991), Bruner et al²⁸ (1993), Mattie et al²⁹ (1991), Gaworski et al³⁰ (1985), MacEwen and Vernot³¹ (1985), and Haun et al³² (1985) for all hepatic health outcomes; therefore, these papers did not undergo study quality evaluation. ^cMacEwen and Vernot³³ (1980) had a partially overlapping data set with Kinkead et al²⁶ (1995), Bruner et al²⁸ (1993), Gaworski et al³⁰ (1985), and Haun et al³² (1985) for some hepatic health outcomes; therefore, this paper underwent study quality evaluation for unique hepatic health outcomes only. ^dMacEwen and Vernot³¹ (1985) had a partially overlapping data set with Kinkead et al²⁶ (1995), Kinkead et al²⁷ (1991), Bruner et al²⁸ (1993), Mattie et al²⁹ (1991), Gaworski et al³⁰ (1985), and Haun et al³² (1985) for some hepatic health outcomes; therefore, this paper underwent study quality evaluation for unique hepatic health outcomes only. ^eDodd³⁴ (1996) and Nordholm et al³⁵ (1999) had an overlapping data set with MacMahon et al³⁶ (1998) for all hepatic health outcomes; therefore, these papers did not undergo study quality evaluation. ^fMattie et al³⁷ (2023) had an overlapping data set with Sterner et al³⁸ (2015) for all hepatic health outcomes; therefore, this paper did not undergo study quality evaluation. ^gMattie et al³⁹ (2020) had an overlapping data set with Sterner et al⁴⁰ (2015) for all hepatic health outcomes; therefore, this paper did not undergo study quality evaluation. ^hSterner et al⁴¹ (2020) had a partially overlapping data set with Wong et al⁴² (2013) for some hepatic health outcomes; this paper underwent study quality evaluation for unique hepatic health outcomes only.

Liver Histopathology

Liver histopathology was examined in 23 animal studies, with several studies showing increased incidence or severity of non-neoplastic lesions related to dermal, oral, or inhalation jet fuel exposure (Supplemental Digital Content, Table S4, http://links.lww.com/JOM/C308).^{19,20,26–30,32,43,44,46,48} Several of these studies observed changes in liver histopathology in animals following jet fuel inhalation exposure. Changes in female mice included increased liver inflammation,²⁷ lymphocytic inflammatory infiltrates,²⁸ hepatocellular vacuolization,²⁶ hepatocellular vacuolization and clear cell focus,³⁰ and fatty change.^30,32 In rats, changes included increased dilated sinusoids, cytoplasmic clumping, and fatty hepatocytes⁴⁴; basophilic foci²⁹ in males; nodular hyperplasia in females²⁸ (hepatocyte hypertrophy)⁴⁶; and hepatocellular vacuolization³⁰ in males and females. One study observed increased fatty liver in male hamsters,³² and one study observed an increase in glycogen accumulation in male and female dogs.³⁰ The incidence of bile duct hyperplasia with periportal fibrosis was increased in male and female rats exposed to JP thermally stable for 1 year and then euthanized 1 year post-exposure.²⁷ However, for male rats, authors attributed the high incidence and severity of these lesions in all groups primarily to age and strain, citing that the incidence of bile duct hyperplasia in 18-month male F-344 rats can be as high as 98%.

Three studies examined dermal exposure to jet fuels in rodents.^43,48,49 Larabee et al⁴³ (2005) observed spotty, isolated hepatic cell death in male rats following short-term dermal exposure to JP-8, and the National Toxicology Program⁴⁸ (1986) reported increased hepatic karyomegaly and liver amyloid in male and female mice following chronic (13 weeks for hepatic karyomegaly and 90 to 103 weeks for liver amyloid) dermal JP-5 exposure. In contrast, Clark et al⁴⁹ (1988) observed no hepatic histopathological changes in male or female mice following chronic dermal exposure to JP-4 or Jet-A.

Two studies examined oral exposure to jet fuels in male rats, including a study of petroleum and shale JP-5¹⁹ and a study of JP-5 and various shale JP-5 derivatives.²⁰ Both studies qualitatively reported increased cytoplasmic vacuolization of periportal hepatocytes, mitotic figures, and necrosis and/or pyknosis in all jet fuels examined.

By contrast, several studies did not observe changes in liver histopathology related to jet fuel exposure. Ten studies showed no change in liver histopathology in rats and/or mice following inhalation exposure to various jet fuels,^{19,26,33,38,40–42,45,50,52} as did three inhalation studies in dogs.^26,32,33 One study observed no changes in female rats following chronic oral exposure to JP-8.⁵¹ Similarly, another study found no effects in fathead minnows.⁵³

Liver Weight

Twenty-three rodent studies examined the effects of jet fuel exposure on liver weight (Supplemental Digital Content, Table S4, http://links.lww.com/JOM/C308). Increased liver weights were observed in rodents following inhalation exposure to jet fuels.^{27–29,31,42,47,51,52,54,56,57,67} Kinkead et al⁵⁴ (1974) reported significant increases in absolute and relative liver weights of male rats following chronic inhalation exposure to JP-4, while Mattie et al²⁹ (1991) reported significant increases following subchronic exposure to JP-8. A second chronic inhalation study reported increased absolute liver weights in female rats, but not male rats, exposed to JP-7.²⁷ In a subchronic study, Wong et al⁴² (2013) exposed male and female rats to HEFA-C jet fuel and observed a significant increase in absolute and relative liver weights of females, although there were no changes observed in male rats. In a second subchronic inhalation study,⁴⁵ significant decreases in absolute and relative liver weights were observed in male rats following exposure to synthetic jet fuels, yet no changes were observed in female rats. Similarly, a decrease in absolute liver weights was observed in male rats and not female rats after a subchronic exposure to JP-4.²⁶ In a study by Mattie et al⁴⁶ (2011), a significant decrease in absolute liver weights was observed in male rats, but not female rats, following a short-term exposure to S-8. No exposure-related changes in liver weights were observed in a subchronic inhalation study of Gevo ATJ SPK⁴⁰ or another subchronic inhalation study of JP-5³⁰ in male and female rats.

Two studies evaluated rats following subchronic, oral exposure to JP-8.^47,51 Mattie et al⁵¹ (2000) observed an increase in absolute and relative liver weights of female rats. In a separate study, Mattie et al⁴⁷ (1995) reported a significant increase in relative liver weights and a significant decrease in the body weights of male rats, but no changes in absolute liver weight. Several studies also evaluated the effects of short-term gavage exposure to JP-8 in female B6C3F1 and/or DBA/2 mice.^56,57,67 An increase in relative liver weights was observed in B6C3F1 mice.⁵⁷ Although absolute liver weight was not reported, the authors noted an increase in body weight with increasing exposure concentration, which they concluded may have resulted from the increased liver weight. Likewise, Dudley et al⁶⁷ (2001) observed increased relative liver weights in both B6C3F1 and DBA/2 mice following oral jet fuel exposure that were not confounded by decreased body weights, as body weight was significantly increased in the B6C3F1 mice and unchanged in the DBA/2 mice. Consistent with these results, an increase in relative liver weight was also reported by Peden-Adam et al⁵⁶ (2001) in B6C3F1 mice with no observed changes in body weight.

Some studies reported conflicting effects of jet fuel exposure, with differences occurring between sexes and across time points.^{26–29,31,41,42,45,46,52} In a study by Sweeney et al⁵² (2013), Sprague-Dawley rats exhibited a significant decrease in absolute liver weight 24 hours after Jet-A exposure, whereas an increased relative liver weight (but not absolute liver weight or body weights) was observed 14 days post-exposure; Jet-A exposure did not affect liver weight in F-344 rats. Sterner et al⁴¹ (2020) and Wong et al⁴² (2013) conducted acute and subchronic studies, respectively, in which male and female rats were exposed to HEFA jet fuels. Following the acute exposure, a decrease in relative liver weight was reported, whereas following the subchronic exposure, increases in relative liver weights were observed in female rats only. MacEwen and Vernot³¹ (1985) reported increased absolute relative liver weights in male F-344, Wistar, and Osborne-Mendel rats following subchronic exposure to shale-derived JP-4, although the effects did not persist, post-exposure. Similarly, Mattie et al²⁹ (1991) reported increased absolute and relative liver weights in male and female rats following subchronic exposure, although these effects generally disappeared in the post-exposure period. Bruner et al²⁸ (1993) conducted a chronic experiment with male and female rats exposed to JP-4 for a year and found that relative liver weights in male rats significantly increased after 1 year of JP-4 exposure, while no changes were observed in absolute liver weights, body weights, or female rats. However, both relative and absolute liver weights in male rats were decreased 1 year after the exposure period. Sex-specific differences were also observed in several studies.^{26,27,42,45,46} Other studies that evaluated liver weight in rodents^{33,36,38,40,49,55} or other animal models^26,33 reported no significant differences in liver weight following exposure to jet fuels, regardless of type of fuel or duration of exposure.

Clinical Pathology

Epidemiology

Three primary epidemiologic studies examined the association between jet fuel exposure and liver enzymes (Supplemental Digital Content, Table S5, http://links.lww.com/JOM/C309). One study compared fuel-filling attendants and office workers in the Danish Air Force and observed no difference between these groups in serum aspartate aminotransferase (AST) or alkaline phosphatase (ALP) during a period of work and following 2 to 4 weeks of vacation.⁶⁸ Tu et al⁶⁰ (2004) observed no difference between exposed and unexposed US Air National Guard members in AST, alanine transaminase (ALT), or gamma-glutamyl transferase (GGT). One cohort study of active-duty and civilian personnel at Hill Air Force Base observed no differences in ALT, AST, or ALP during the transition of use of JP-4 to JP-8 and at 3, 6, and 18 months afterward.⁵⁹

Animal Toxicology: Liver Enzymes

Twenty animal studies examined the effects of jet fuel exposure on liver enzymes (Supplemental Digital Content, Table S4, http://links.lww.com/JOM/C308). Serum ALT was measured in all 20 studies, whereas serum AST and ALP were measured in 19 and 17 of these studies, respectively. Observed alterations in liver enzymes were inconsistent across studies, potentially due to differences in experimental design, jet fuel type, and sex.

Animal studies that evaluated changes in ALT and AST following jet fuel exposure reported mixed findings. Mattie et al⁴⁷ (1995) and Bogo et al¹⁹ (1983) reported a significant increase in serum ALT in male rats after subchronic gavage exposure to JP-8 or JP-5, respectively. Parker et al²⁰ (1981) also reported significant increases in ALT in male rats after an acute gavage exposure to JP-5 and three shale derivatives.²⁰ In contrast, other studies reported significant decreases in serum ALT following exposure to jet fuels in male and/or female rats,^28–31,45 although this effect was sometimes inconsistent between time points and jet fuels studied.^30,31 Mattie et al⁴⁵ (2011) acknowledged that the observed decrease in ALT levels likely did not have toxicological significance and, taken together with an observation of decreased weight gain, was possibly related to nutritional deficits. Several studies, representing a range of different exposure paradigms, reported no change in serum ALT following jet fuel exposure in rats,^{26,33,36,38,40–42,51,52} dogs,^{26,27,33,36,38,40–42,51,52} or monkeys.⁵⁴

Four studies reported a significant increase in serum AST in male rats: one following chronic inhalation exposure to JP-4,²⁸ one following subchronic gavage exposure to JP-8,⁴⁷ one following short-term gavage exposure to petroleum and shale JP-5,¹⁹ and the fourth following acute gavage exposure to JP-5 or various shale jet fuels.²⁰ However, three studies reported decreases in AST, but these changes were inconsistent between sex, time point, and jet fuels studied.^29–31 Other studies that measured serum AST reported no changes after jet fuel exposure, whether evaluating rats^27,38,40 or dogs.^26,32,33

Of the 17 studies that examined serum ALP, eight of them reported significant differences following inhalation of jet fuel in rats.^{26–31,33,45} In six studies, serum ALP was significantly decreased,^{26,28,30,31,33,45} but these changes were often inconsistent between sex and time point.^26,30,31 However, as with their finding for serum AST, Mattie et al⁴⁵ (2011) stated that this result likely does not carry toxicological significance and might instead be due to malnutrition. In contrast, Mattie et al²⁹ (1991) reported significant increases in ALP in male and female rats after 90 days inhalation exposure to JP-8; however, by 21 months post-exposure, no significant changes were reported. Another study reported significant increases in ALP in male and female rats after chronic inhalation exposure to JP-7, but the increases were inconsistent between doses and not considered exposure-related by the study authors.²⁷ Other studies reported no significant differences in serum ALP following jet fuel exposure in rats,^{26,36,38,40–42,51,52} dogs,^26,32,33,54 or monkeys.⁵⁴

Animal Toxicology: Other Serum Biomarkers

In addition to liver enzymes, jet fuel exposure–associated changes in several other serum biomarkers were analyzed (Supplemental Digital Content, Table S4, http://links.lww.com/JOM/C308). These varied across studies but included total bilirubin, albumin, albumin/globulin (A/G) ratio, total protein, and GGT. Similar to the situation with liver enzymes, changes in serum biomarkers varied across study designs.

Fourteen studies assessed the impact of jet fuel exposure on serum total bilirubin, with only four reporting significant increases^28,29,42,47 following exposure. Bruner et al²⁸ (1993) reported significant increases in female rats, but not male rats, following chronic inhalation exposure to JP-4. However, Mattie et al⁴⁷ (1995) and Wong et al⁴² (2013) reported increases in male rats but not female rats, following subchronic gavage of JP-8 or inhalation of HEFA-C, respectively. Mattie et al²⁹ (1991) reported no changes following a 90-day inhalation exposure to shale JP-8 and decreases at 9 months post-exposure in female rats, but significant increases were noted in male rats 21 months post-exposure. Other studies reported no changes in serum bilirubin.^{26,27,30,32,33,38,40,41,51,52}

Many studies also assessed the effect of jet fuel exposure on serum albumin levels in rats. Bruner et al²⁸ (1993) reported a significant decrease in serum albumin in female rats only following chronic inhalation exposure to JP-4. Mattie et al⁴⁵ (2011) and Gaworski et al³⁰ (1985) also reported significantly decreased serum albumin levels in both male and female rats exposed subchronically to S-8 or petroleum JP-5³⁰ via inhalation. However, the effects in Gaworski et al³⁰ (1985) were transient in females, and they also reported a significant decrease in males, but not females, subchronically exposed to shale JP-5 via inhalation. Sex-specific differences were also observed in other subchronic inhalation studies of jet fuels, whereby Kinkead et al²⁶ (1995), MacEwen and Vernot³¹ (1985), and Mattie et al²⁹ (1991) all reported significant decreases in albumin in either males or females, either at 9 or 19 months post-exposure, but effects were inconsistent between time points. Wong et al⁴² (2013) reported significantly increased serum albumin only in male rats following subchronic inhalation exposure to HEFA-C. Other studies reported no changes in serum albumin in rats^38,40 or dogs.^26,30,33

In addition to evaluating serum albumin levels, some studies evaluated the effects of jet fuel exposure on the A/G ratio, with five reporting significant decreases following exposure.^{26,28–30,32} Haun et al³² (1985) reported a decreased A/G ratio following chronic JP-10 exposure via inhalation in male and female dogs, which was statistically significant but was noted to still be within the reference range.³² Bruner et al²⁸ (1993) observed a decreased A/G ratio in female rats only following chronic inhalation exposure to JP-4. Gaworski et al³⁰ (1985) also reported decreased A/G ratio in male and female rats following subchronic inhalation to petroleum and shale JP-5, but there were inconsistent changes in the postexposure period. In contrast, Kinkead et al²⁶ (1995) and Mattie et al²⁹ (1991) reported a decreased A/G ratio in male, but not female rats, following subchronic inhalation exposure to either JP-8 or JP-4, although these effects were only observed at 9 or 19 months post-exposure, not immediately following exposure termination.^26,29 The remaining studies reported no jet fuel–related changes in the A/G ratio in rats^27,31,54 or dogs.^30,33

In addition, numerous studies measured serum total protein following jet fuel exposure, with several reporting significant changes in total protein and one reporting non-significant changes. Four studies indicated that inhalation exposure to jet fuels increased serum total protein in female dogs chronically exposed to JP-10³² and male rats chronically exposed to JP-7²⁷ or subchronically exposed to HEFA-C.⁴² Furthermore, Kinkead et al²⁶ (1995) reported increased total protein, but only in female rats subchronically exposed to JP-4 and only at 19 months post-exposure. Two other rodent studies reported significant decreases in total serum protein following subchronic exposure to S-8 in male rats only⁴⁵ and after short-term exposure to Jet-A in female rats.⁵² In addition, four studies reported sex-specific decreases in total protein evaluated in subchronically exposed male or female rats, but effects were inconsistent between time points.^26,29–31 In contrast, several studies reported no changes in serum total protein.^{28,33,38,40,41,51,54} Only two studies examined associations between jet fuel exposure and serum GGT levels; both reported no significant changes.^41,51

Mechanistic Data

Nine studies evaluated how jet fuel exposures may impact the hepatic system using a mechanistic approach (Supplemental Digital Content, Table S6, http://links.lww.com/JOM/C310), with eight studies evaluating JP-8 exposures, one of the studies also evaluating Jet-A exposures, and one study evaluating occupational exposure to unspecified jet fuels. Three studies evaluated protein expression changes in the liver in response to JP-8 exposure in either male rats^43,62 or female mice and a human hepatoma cell line.⁶⁷ In targeted protein expression analyses, Larabee et al⁴³ (2005) found significant increases in HSP70 protein in liver tissue in exposed rats. Dudley et al⁶⁷ (2001) reported no differences in aryl hydrocarbon receptor or cytochrome P450 1A1 expression in either mice or the human hepatoma cell line following JP-8 exposures. Witzmann et al⁶² (2000) evaluated global protein expression changes in rat liver tissue and reported that the protein Lamin A was upregulated, although statistical significance was not reached.

Two studies examined changes in glutathione (GSH), an indicator of oxidative stress, in response to JP-8 exposures in male rats.^69,70 Fechter et al⁶⁹ (2007) reported decreases in GSH levels in JP-8–exposed rats immediately after exposure, although a recovery to baseline levels was observed 3 hours post-exposure. Fechter et al⁷⁰ (2008) reported no significant differences in GSH levels.

Other mechanisms explored included xenobiotic metabolism, cell viability, and biomarkers of tissue damage. JP-8 exposures, ranging from 10 to 80 μg/mL in a rat hepatoma cell line, resulted in no significant changes in apoptotic cell death.⁷¹ However, Grant et al⁷² (2000) determined that the IC₅₀ concentration, which is the concentration at which exposure reduces cell viability to 50%, for JP-8 or Jet-A exposure in the rat hepatoma cell line was approximately 13 μg/mL for both jet fuel types. Edwards et al⁷³ (2005) evaluated the effects of JP-8 exposure in human liver microsomes and found that JP-8 was able to inhibit the metabolism of testosterone, estradiol, carbaryl, and N,N-diethyl-m-toluamide (DEET). However, one study compared fuel-filling attendants and office workers in the Danish Air Force and observed no difference between these groups in antipyrine clearance, a measure of metabolism in the liver, during a period of work and following 2 to 4 weeks of vacation.⁶⁸

DISCUSSION

Epidemiologic and Toxicological Data Summary and Synthesis

There was indeterminate epidemiologic evidence of an association between jet fuel exposure and renal health outcomes based on four low-confidence studies (Table 1 and Supplemental Digital Content, Table S7, http://links.lww.com/JOM/C179). Studies assessing serum and urinary biomarkers of renal function observed no significant associations with jet fuel exposure. Yet, uncertainty remains due to the limited number of studies evaluating renal health outcomes in humans and the lack of high-quality studies.

TABLE 1.

Summary of the Epidemiologic and Animal Toxicological Evidence Synthesis, and Evidence Integration Strength of Evidence Judgment Calls for Renal Health Outcomes

Evidence Stream	Strength of Evidence Judgment	Description
Epidemiologic	Indeterminate	Evidence of an association was limited and inconsistent; very few studies were available.
Animal toxicological	Moderate	Primarily consistent evidence of an association between exposure and renal health outcomes supported by at least one high- and medium-confidence study that did not reach the degree of certainty required for robust.
Epidemiologic, animal toxicological, and mechanistic	Evidence suggests	An evidence base that suggested that jet fuel exposure might cause renal health effects in humans, but there were very few epidemiologic studies that contributed to the evaluation, and the evidence in animal toxicological evidence was inconsistent.

In contrast to the limited human data available, the animal studies supporting jet fuel–induced changes to the renal system present moderate evidence (Table 1 and Supplemental Digital Content, Table S7, http://links.lww.com/JOM/C179). Histopathological alterations of the kidney were frequently observed, with most studies reporting a higher incidence and severity of non-neoplastic lesions in male rodents and a less robust impact noted in females. Notably, these included non-neoplastic lesions, such as mineral deposits, hyaline droplet accumulation, tubular damage, and hyperplasia. Several authors associated these lesions with nephropathy, specifically chronic progressive glomerulonephropathy.^28,32,38 Nephropathy was commonly observed, with prolonged exposure to jet fuels resulting in increasing severity. As discussed in some of the studies identified in this review^28,32,38 as well as the US EPA,⁷⁴ the male rat–specific protein α_2u-globulin leads to hyaline droplet formation and cytotoxicity, ultimately resulting in nephropathy. More specifically, α_2u-globulin binds to hyaline droplet-inducing chemicals or their metabolites, forming a degradation-resistant complex within renal proximal tubules that triggers hyaline droplet formation and a nephropathic response in male rats. This includes sustained increases in cell turnover, molecular alterations in kidney cells, tubule dilation, papillary mineralization, and tubule hyperplasia.⁷⁴

Consequently, the relevance of these histopathological changes found in male rodents to human kidneys remains uncertain. Some histopathological changes were noted to be caused by jet fuel, while others were deemed unrelated to the exposure. For instance, Haun et al³² (1985), Sterner et al³⁸ (2015), and Bruner et al²⁸ (1993) reported that chronic progressive nephropathy and the associated kidney lesions are common spontaneous effects observed in aging rats, particularly in males, due to α_2u-globulin. Tubular damage/degeneration and hyaline droplet accumulation were also often reported as being spontaneous lesions and commonly observed with nephropathy/chronic progressive glomerulonephropathy in aging rats, particularly males.^28,32,40 Nonetheless, the incidence and/or severity was frequently increased with jet fuel exposures. In female mice, amyloid formation was observed in the kidneys following exposure to jet fuel (NTP 1986).⁴⁸ In addition, female rats exhibited higher incidence of non-neoplastic lesions in the kidneys, including tubular pigmentation, mineralization, periglomerular fibrosis, and inflammation, a key characteristic associated with cancer.^32,38,40 Taken together, these findings suggest that the effects observed may not solely be due to the normal aging process and increased α_2u-globulin levels in male rats.

Complicating the interpretation of the histopathological findings, inconsistent findings were reported in serum and urinary biomarkers, such as BUN, UA, and CREA, which are waste products excreted by the kidneys, and associated with reduced glomerular filtration rates and kidney dysfunction,^75,76 and CK, which is associated with acute kidney injury.⁷⁷ The majority of studies did not report significant changes in serum biomarkers of renal toxicity, although both serum and urinary biomarkers were altered in several rodent studies. Notably, CREA and/or BUN was increased in male rats^20,27,47 but decreased in female rats.^28,40,41 Urine pH was decreased in male and female rats,^41,47 and urinary ketones, leukocytes, and blood were increased in male rats.⁴¹ Overall, although the significant findings were inconsistent and the number of studies assessing urinary biomarkers was limited, these changes in biomarkers of renal toxicity were coherent with histopathological observations. At the organ level, 13 out of 23 studies that assessed kidney weight reported an increase in absolute and/or relative kidney weights, with those effects primarily being observed in rat studies. Collectively, the epidemiologic evidence and animal toxicological data suggest that exposure to jet fuel may induce nephrotoxicity.

Similar to the evidence in human studies on renal health outcomes, evidence evaluating the association between jet fuel exposure and hepatic health outcomes in humans was indeterminate based on the limited number of studies and the lack of medium- or high-confidence studies (Table 2 and Supplemental Digital Content, Table S8, http://links.lww.com/JOM/C180). No significant effects were reported in three low-confidence studies examining associations between short-term and long-term jet fuel exposures and biomarkers of hepatic function, including AST, ALT, ALP, and GGT.

TABLE 2.

Summary of the Epidemiologic and Animal Toxicological Evidence Synthesis, and Evidence Integration Strength of Evidence Judgment Calls for Hepatic Health Outcomes

Evidence Stream	Strength of Evidence Judgment	Description
Epidemiologic	Indeterminate	Evidence of an association was limited and inconsistent; very few studies were available.
Animal toxicological	Slight	Studies reported a link between exposure and health outcome with considerable uncertainty.
Epidemiologic, animal toxicological, and mechanistic	Evidence suggests	An evidence base that suggested that jet fuel exposure might cause hepatic health effects in humans, but there were very few epidemiologic studies that contributed to the evaluation, and the evidence in animal toxicological evidence was weak or conflicting.

There was slight animal toxicological evidence that jet fuel exposure results in hepatotoxicity (Table 2 and Supplemental Digital Content, Table S8, http://links.lww.com/JOM/C180). The available data suggest that jet fuel exposure can lead to hepatomegaly, as evidenced by increased liver weights and histopathological alterations. The evidence was strongest for increased liver weights, which was observed in most of the studies. Some studies reported changes in absolute liver weight that were considered secondary to changes in body weight and deemed unrelated to exposure. However, increased liver weight was supported by histopathological findings, with some studies reporting hepatocyte hypertrophy. Other notable, non-neoplastic lesions included increased liver inflammation, hepatocellular vacuolization, dilated sinusoids, hyperplasia, and hepatic cell death. Fatty changes, or fatty liver, were also commonly observed in rodent studies,^27,28,32,44 although some study authors noted that these changes are also commonly observed in aging animals and dismissed them as not related to exposure.^27,28 The animal toxicological data suggested that the effects on liver histopathology could vary significantly based on several factors, such as the duration of exposure, dosage, and the specific type of fuel used. Increased ALT, AST, and ALP enzyme levels in serum are considered markers of liver injury and were inconsistently altered. Similar results for other hepatic biomarkers, such as bilirubin, albumin, and total protein, were also observed. While the histopathological changes and increased liver weights may suggest hepatic damage, inconsistent data regarding serum biomarkers did not fully support this conclusion. Taken together, the epidemiologic evidence and animal toxicological data suggest that exposure to jet fuel may induce hepatotoxicity.

Mechanistic Data Summary

Mechanistic data supporting apical endpoints of jet fuel–induced renal damage were limited by the number of studies and the fact that studies were primarily performed in male rats (Supplemental Digital Content, Table S3, http://links.lww.com/JOM/C307). Observations of renal injury via increased hyaline droplet accumulation were supported by mechanistic evidence of increased α_2u-globulin protein.^38,40,42,44 This protein produces hyaline droplets and can result in an elevated number of renal tubule tumors.²⁸ Importantly, this mechanistic finding is supportive for the apical renal outcomes that are indicative of renal injury observed only in male rats and cannot be applied to other species or sexes, thus limiting the generalizability of these results. Reports of dysregulated protein expression, including increased HSP70, observed in kidney tissue provided additional mechanistic support for jet fuel–induced renal damage,⁴⁴ although only one study evaluated this endpoint. These findings demonstrate the ability of jet fuel exposures to enhance an inflammatory response in the kidneys, thus potentially supporting the apical endpoints, including non-neoplastic lesions and urinary and serum biomarkers.

Mechanistic data supporting observations of jet fuel–induced hepatic injury in animals were also limited (Supplemental Digital Content, Table S6, http://links.lww.com/JOM/C310). One study evaluated aryl hydrocarbon receptor or cytochrome P450 1A1 expression in response to JP-8 exposure in both an animal model and a cell culture model and observed no changes.⁶⁷ Regarding the other mechanistic findings, various limitations were noted, such as the small number of studies evaluating mechanistic endpoints, inconsistency of results among studies that evaluated similar endpoints, and limited types of jet fuels evaluated. Inconsistent effects were observed for oxidative stress and cell viability, as studies demonstrated both decreases in GSH and increased cell death in response to JP-8 exposure, as well as non-significant findings for these endpoints.^69–71

Evidence Integration

Considering the available evidence from human, animal, and mechanistic studies, evidence suggests that exposure to jet fuels may cause nephrotoxicity in humans under relevant exposure circumstances (Table 1 and Supplemental Digital Content, Table S7, http://links.lww.com/JOM/C179). This conclusion is based primarily on consistent evidence of alterations in kidney histopathology in animal toxicological studies. The key findings include nephropathy and other histopathological changes associated with nephropathy/chronic progressive glomerulonephropathy in male rats and fibrosis and inflammation in female rats. Furthermore, changes in organ weights and serum biomarkers in animal toxicological studies, as well as mechanistic evidence, support the observed histopathological changes. The available epidemiologic information to support these findings was limited.

Similarly, based on the evidence from human, animal, and mechanistic studies, evidence suggests that exposure to jet fuels may cause hepatotoxicity in humans under relevant exposure conditions (Table 2 and Supplemental Digital Content, Table S8, http://links.lww.com/JOM/C180). This conclusion is based primarily on evidence from animal toxicological studies, including changes in liver weight and histopathology. The available epidemiologic and mechanistic information to support these findings was limited.

Together, the liver and kidneys are key organs in maintaining a body's homeostasis. Their complementary functions, metabolism and excretion, are essential for preventing the accumulation of harmful substances that can lead to cellular damage, organ failure, and systemic toxicity. Damage to either the liver or the kidneys can significantly impair their normal functions, with potentially severe, systemic, long-term consequences. Understanding the impact of jet fuel exposure on these organs is crucial to enhance the understanding of how jet fuel exposure can impact an individual's health in both the short and long term.

Gaps and Limitations

We did not assess the differing composition among the jet fuels or how this may have impacted the results, which present one potential limitation of this review. The composition of jet fuels varies slightly depending on their specific mission-related use, particularly in different military settings, and each component could differentially affect the liver and kidneys. However, most jet fuels are kerosene-based, with smaller quantities of toxic hydrocarbons (such as benzene, toluene, and naphthalene) present as well as non-hydrocarbon performance additives. Due to the overall similarities in composition, all jet fuels were grouped together in this review.

Although animal toxicological data suggest potential nephrotoxicity and hepatotoxicity from jet fuel exposure, inconsistent findings and a lack of high-quality studies reported in the literature on the hepatic and renal effects in humans limit the ability to draw definitive conclusions about exposure-driven health outcomes in the military population. Further epidemiologic research or supporting evidence is needed to corroborate the observed hepatic and renal impacts reported here and to enhance the consistency and clarity of these associations. For instance, information on worker protections was not reported in most studies, making evaluation of current worker protections in the context of hepatic and renal effects difficult. For example, one study described detailed protective measures for exposed personnel (fitted respirators, supplied protective clothing, dedicated laundering facilities, etc), but aromatic and aliphatic hydrocarbons were detected in exhaled breath measurements, suggesting exposure to jet fuel in this group despite protective measures.⁶⁰ In contrast, most studies did not provide information on protective measures or provided information on protective measures with occupational exposure measurements for only a subset of the population.⁶⁸ In addition, human studies with detailed data on clinical pathology, including serum biomarkers of kidney and liver injury (e.g., BUN, CREA, CK, ALT, and AST), and histopathology from tissue biopsies would improve our understanding of the hepatic and renal effects of jet fuel exposure.

For animal toxicology studies, uncertainty remains due to the inconsistent direction of effects across types of jet fuels, sex, and species for some endpoints. In addition, exposure paradigms and doses used for the risk assessment of jet fuel exposure in animal studies may not correspond to the actual exposure conditions encountered by military personnel or other populations. This limitation hinders the capacity to extrapolate findings from animal models to humans. Therefore, future research should focus on human-relevant exposure paradigms, including chronic low-dose studies. Further research that expands on the diversity in animal species used (beyond rodents), the number of studies examining specific health outcomes (particularly serum biomarkers of renal and hepatic toxicity), and the number of studies examining each type of jet fuel (and their additives) would also improve understanding of the hepatic and renal effects of jet fuel exposure.

In sum, the available evidence suggests that jet fuels may cause liver and kidney toxicity. Although driven largely by data from animal toxicological studies, consistency of histopathological changes, organ weights, and serum biomarkers of liver and kidney function, bolstered by mechanistic evidence, lends support for this conclusion. Additional research on specific human hepatic and renal effects is needed to confirm these associations.