Assessing the Carcinogenic Potential of Jet Fuels

The epidemiologic and toxicological evidence, supported by mechanistic data, suggest that there may be an increased risk of various cancers, including kidney, bladder, and skin cancers in humans and animals exposed to jet fuels. This information may help inform patient care related to exposures and cancer screening.

Abstract

Objective

The aim of the study was to determine whether exposures to jet fuels lead to cancer-related health effects.

Methods

A systematic literature review was conducted following the US EPA’s IRIS handbook, incorporating epidemiologic, animal toxicological, and mechanistic studies. The carcinogenic potential of jet fuel was assessed according to EPA’s 2005 Guidelines for Carcinogen Risk Assessment.

Results

Increased risks of various cancers, including kidney, bladder, and skin cancers, were observed in humans and animals exposed to jet fuels, which were supported by mechanistic data.

Conclusions

The available studies provide suggestive evidence of carcinogenic potential for jet fuels. However, uncertainty remains because of to the limited number of high-quality epidemiologic studies and the wide variety of jet fuel types examined. Further research is needed to establish a more definitive link between jet fuel exposure and cancer risk.

LEARNING OUTCOMES

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

• Summarize the epidemiologic, animal toxicological, and mechanistic evidence regarding cancer outcomes associated with jet fuel exposure.

• Evaluate the state of the scientific literature on cancer health effects of jet fuel exposure and discuss data gaps and limitations that present an opportunity for future research.

Jet fuel is the largest single source of chemical exposure encountered by US military personnel.¹ Service members responsible for fueling, defueling, and maintaining aircraft, transporting fuel, and maintaining storage tanks are at higher risk of occupational exposure to jet fuel.^2–4 However, the risk of exposure is not limited to aviation-related occupations, since jet fuel is used to power ground vehicles, generators, and stoves in operational settings.^1,4,5 Despite the prevalence of jet fuel hazards in military environments, the long-term health effects of occupational exposure are not well understood.

Jet fuels are complex mixtures comprised of hundreds of aliphatic and aromatic hydrocarbons (over 98% kerosene by volume [v/v]) and nonhydrocarbon performance additives. Commercial (eg, Jet A) and military variants (eg, Jet Propellant-4 [JP-4], Jet Propellant-5 [JP-5], Jet Propellant-8 [JP-8]) vary in their specific additive formulations, which are tailored to meet unique performance requirements.⁵ While many of the minor constituents of jet fuel are chemicals with well-established health effects, including known (benzene) and possible carcinogens (ethylbenzene and naphthalene), the impacts of these components as a mixture are not well defined.^6,7

Multiple previous reviews found only sparse epidemiologic data on the long-term health effects of jet fuel exposure.^1,4,8,9 At the time of their 1995 review, the Agency for Toxic Substances and Disease Registry (ATSDR) found no data regarding cancer in humans after inhalation, oral, or dermal exposure to JP-4 or JP-7.⁹ In 2003, the National Research Council (NRC) did not identify any long-term epidemiologic studies of cancer outcomes following JP-8 exposure,⁴ and in 2017, ATSDR determined that available data on the long-term effects of JP-5, JP-8, and Jet A were still too limited to determine their potential carcinogenicity.⁸ These reviews also considered evidence from animal toxicological studies and found it insufficient to make a determination about the potential for jet fuels to cause cancer in humans.^1,4,8,9

The current review extends previous efforts by integrating new findings and adopting a broader scope. Studies on various jet fuels, including JP-4, JP-5, JP-7, and JP-8, were assessed, and multiple routes of exposure were considered. The review evaluated a range of cancer outcomes, incorporating both animal toxicological and mechanistic data to address gaps in the epidemiologic evidence. Utilizing methods adapted from the US Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS)¹⁰ and aligning with EPA’s 2005 Guidelines for Carcinogen Risk Assessment,¹¹ this review employed a descriptive weight of evidence evaluation to characterize the potential carcinogenic effects of occupational exposure to jet fuel. This approach allowed for a nuanced understanding of the strength and consistency of findings across multiple evidence streams.

METHODS

This systematic literature review was designed to capture evidence of the health effects of jet fuel exposure drawing from research in humans, animals, and mechanistic models. Review methods were adapted from the EPA’s IRIS assessment framework, as outlined in the IRIS Handbook.^10,12 The following is a summary of the methods utilized to identify, evaluate, and synthesize the available evidence related to the association between jet fuel exposure and effects on cancer outcomes in humans. A detailed description of the methods applied in this review is available in Bergeron et al (2025).¹³

Literature Search Strategy

Literature searches identified relevant epidemiologic, animal toxicological, and mechanistic studies published through March 2025. References were identified in searches of four categories of bibliographic sources: (1) databases of scientific literature (PubMed and EBSCOhost); (2) gray literature, including technical reports from government agencies and authoritative bodies; (3) expert-identified publications and reports; and (4) references cited in selected secondary reviews of epidemiologic and animal toxicological data.

Inclusion and Exclusion Criteria

Populations, Exposures, Comparators, and Outcomes (PECO) criteria provided a framework for the literature search strategy and were used to define inclusion/exclusion criteria for screening search results.¹⁴ For epidemiologic studies, the relevant population was any human population (eg, military, occupational, general population) in any life stage; for animal toxicological studies, the relevant population was any vertebrates in any life stage. For mechanistic studies, the relevant population included samples from any human population in any life stage, samples from vertebrates in any life stage, or ex vivo or in vitro samples, as well as in silico models. Relevant exposures included any exposure to jet fuels by any route of exposure for any length of time. Relevant comparators were reference populations not exposed or exposed to lower levels of jet fuels. For the evaluation of cancer outcomes, relevant outcomes included any neoplasm in epidemiologic and toxicological studies, as well as cellular, biochemical, and molecular changes related to jet fuel exposure and carcinogenic-related toxicity in mechanistic studies. Case reports, case studies, case series, and secondary reviews were included as supplemental information in this review. They are discussed as part of the evidence synthesis but do not contribute to the weight of evidence determination.

Literature Screening and Data Extraction

For each reference identified as PECO-relevant in title/abstract screening, the full text was retrieved and advanced to full-text screening. Screenings were performed by two independent reviewers using structured forms, with a process for conflict resolution by a subject-matter expert. References identified as not relevant during the screening process did not move forward in the review process. References that reported findings from the same study population (ie, overlapping studies) were considered on a case by case basis. When the studies reported results on the same outcome, using the same methods and comparison groups, then only findings from the study with the longest follow-up underwent study quality evaluation and data extraction to avoid misrepresenting the amount of evidence available. When studies reported on different endpoints from the same study population or used different comparison groups, they were considered independently. Data extraction was conducted on all relevant primary epidemiologic, animal toxicological, and mechanistic studies with all health outcomes considered for extraction, regardless of magnitude or significance of effect or study quality. Extraction was completed by one reviewer and verified by a second senior reviewer, a deviation from the EPA’s IRIS Handbook. Case reports, case studies, case series, secondary reviews, and mechanistic studies had only qualitative information extracted to support the primary evidence.

Study Quality Evaluation

All epidemiologic and animal toxicological studies identified as PECO-relevant after full-text screening underwent study quality evaluation to assess their risk of bias and sensitivity to detecting changes in the health outcomes under consideration. Evaluation was conducted by a trained reviewer and verified by a second senior reviewer, and any disagreements were discussed with a third subject matter expert, a deviation from the EPA’s IRIS Handbook. For each study quality domain, a primary reviewer 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.¹⁰ Overall study confidence (a rating of high, medium, low, or uninformative) was determined by considering the strengths and limitations of the individual evaluation domains.¹⁰ Some studies assessing multiple endpoints had different study quality ratings for each endpoint, and this resulted in multiple overall confidence ratings within a single study. The overall confidence rating reflects interpretations of the potential influence of risk of bias or sensitivity on the results, including the direction and magnitude of such influence across all domains. Case reports, case studies, case series, secondary reviews, overlapping references, and mechanistic studies did not undergo study quality evaluation. The rationale for study quality ratings is available on Tableau (Seattle, WA) 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

The epidemiologic and animal toxicological evidence were synthesized for each body of evidence considered in the review. Syntheses were based primarily 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 limited available literature) were considered but given lower priority.

Evidence integration combined epidemiologic and animal toxicological evidence by considering several factors, such as the human relevance of animal findings, cross-stream coherence, susceptible populations, biological plausibility, potential mode of action, and supplemental evidence from mechanistic studies. Mechanistic evidence was summarized according to the Key Characteristics of Human Carcinogens (KCCs), a systematic approach to identify, organize, and subsequently summarize mechanistic findings relevant to carcinogenesis, to further support biological plausibility.¹⁵ In brief, the key characteristics (KCs) are as follows: (1) is electrophilic or can be metabolically activated; (2) is genotoxic; (3) alters DNA repair or causes genomic instability; (4) induces epigenetic alterations; (5) induces oxidative stress; (6) induces chronic inflammation; (7) is immunosuppressive; (8) modulates receptor-mediated effects; (9) causes immortalization; and (10) alters cell proliferation, cell death, or nutrient supply. These KCs are further described in Supplemental Digital Content, Table S1 (http://links.lww.com/JOM/C240).

A comprehensive evaluation of jet fuel’s potential carcinogenicity in humans was conducted in accordance with EPA’s 2005 Guidelines for Carcinogen Risk Assessment.¹¹ The evaluation integrated all available epidemiologic, animal toxicological, and mechanistic data to determine the likelihood of jet fuel being a human carcinogen and the specific conditions under which carcinogenic effects might occur. The assessment considered all relevant outcomes identified in the literature and weighed the quality and strength of evidence supporting each outcome. In accordance with the EPA guidelines, a detailed narrative was developed to justify the weight of evidence.

RESULTS

Literature Search and Study Selection

Literature searches returned a total of 4291 references; 621 were deemed relevant during title/abstract screening. Full-text screening yielded 279 references that met the inclusion criteria, including 42 epidemiologic studies, 125 animal toxicological studies, and 113 mechanistic studies. A total of 134 references focused on neoplastic health outcomes or potential for carcinogenicity, including 11 epidemiologic studies (including one study reporting duplicate results), 19 animal toxicological studies (including 7 studies reporting duplicate data), and 83 mechanistic studies (15 addressing genotoxicity and an additional 68 informing the KCCs). Mechanistic studies identified from full-text screening were assessed for outcomes related to the KCs, with most studies reporting on endpoints associated with KC 6 (Induces Chronic Inflammation; n = 27), KC 7 (Is Immunosuppressive; n = 27), KC 2 (Is Genotoxic; n = 15), KC 10 (Alters Cell Proliferation, Cell Death, or Nutrient Supply; n = 12), or KC 5 (Induces Oxidative Stress; n = 14). No studies identified included mechanistic data pertaining to KC 1 (Is Electrophilic), KC 3 (Alters DNA Repair or Causes Genomic Instability), or KC 9 (Causes Immortalization). These data are illustrated in Figure 1.

FIGURE 1.

Reference flow diagram of the search, screening, and selection of cancer 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 studies and 125 animal toxicological references. Of the 279 total relevant references, 134 specifically discussed cancer effects of jet fuel exposure, including 11 epidemiologic references, one case report or case series, 19 animal toxicological references, 83 mechanistic references, and 20 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 animal toxicological 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. ^dOne reference reported on the same epidemiological study of cancer outcomes as other references. After excluding reports of the same data, there were 10 references that reported unique epidemiological evidence in this body of literature. ^eSeven references reported on the same animal toxicological study of cancer outcomes as other references. After excluding reports of the same data, there were 12 references that reported unique animal toxicological evidence in this body of literature. ^fOf the 134 relevant cancer references, 83 references contained relevant mechanistic data that were relevant to the key characteristics of carcinogens as defined by Smith et al. (2016).¹⁵

Data from all steps of the systematic review process were exported into Microsoft Excel and used to create interactive visuals in Tableau, including an Interactive REFerence Flow diagram (I-REFF),¹⁶ study quality evaluation heatmaps with detailed rationales for the overall study confidence ratings of all epidemiologic and animal toxicological studies, and evidence maps for epidemiologic and animal toxicological studies. Data are available for download from the interactive Tableau dashboard at: https://public.tableau.com/app/profile/vha.home/viz/SupportingInformationforVHAJetFuelsReport_17002413903760/ReadMe?publish=yes.

Of the 10 primary epidemiologic studies investigating cancer outcomes related to jet fuel exposure, one was considered medium confidence and nine were considered low confidence (Fig. 2). No epidemiologic studies were considered high confidence. The exposure measurement domain was rated deficient for all 10 studies. Common issues in the low confidence studies included potential for bias due to participant selection, residual confounding, and low sensitivity due to small numbers of jet fuel-exposed participants.

FIGURE 2.

Summary of study quality evaluation results for cancer outcomes for epidemiologic studies of jet fuel exposure. This heatmap provides an overview of the study quality ratings assigned to the 10 epidemiologic studies that reported cancer 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 (ie, good, adequate, deficient, critically deficient) and overall study confidence classification (ie, 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 Handbook¹⁰ and are further discussed in Bergeron et al (2025).¹³ One study was considered medium confidence and nine studies were considered low confidence. ^aBlair et al (1998)¹⁷ had an overlapping dataset with Radican et al (2008)¹⁸ for all cancer outcomes; therefore, this paper did not undergo study quality evaluation.

Twelve primary animal toxicological studies examined the association between cancer-related health outcomes and jet fuel exposure. One study was considered high confidence, nine studies were considered low confidence, and two studies were considered uninformative (Fig. 3). Studies that were considered low confidence or uninformative contained one or more of the following issues: lack of clarity during reporting, lack of details on allocation and randomization of animals into exposure groups, observational biases, contained confounding variables, high levels of attrition, lack of details on jet fuel characterization and administration, lack of sensitivity or specificity of endpoint measurements, or lack of detailed results that reduced the ability to interpret findings. Studies that were found to contain uninformative animal data were excluded from analysis.^29,32

FIGURE 3.

Summary of study quality evaluation results for cancer outcomes for animal toxicological studies of jet fuel exposure. This heatmap provides an overview of the study quality ratings assigned to the 12 animal toxicological studies that reported cancer 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 (ie, good, adequate, deficient, critically deficient) and overall study confidence classification (ie, 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 Handbook¹⁰ and are further discussed in Bergeron et al (2025).¹³ One study was considered high confidence, nine were low confidence, and two were uninformative. ^aMacEwen and Vernot (1985, 1984, 1983, 1982, 1981, 1980, and 1978)^19–25 reported overlapping datasets with Kinkead et al (1995),²⁶ Bruner et al (1993),²⁷ Kinkead et al (1991),²⁸ Mattie et al (1991),²⁹ Gaworksi et al (1985),³⁰ and Haun et al (1985)³¹ for all cancer outcomes; therefore, these papers did not undergo study quality evaluation.

Cancer Findings

Epidemiologic and animal toxicological studies examined the potential association between jet fuel exposure and cancer using a variety of study designs. Outcomes assessed in epidemiologic studies included overall cancer incidence and mortality from any type of cancer and several specific cancer types. Detailed findings from epidemiologic studies are presented in Supplemental Digital Content, Table S2 (http://links.lww.com/JOM/C291). Animal toxicological studies explored various routes of exposure, including dermal, and inhalation, and primarily identified nonmelanoma-type dermal and kidney cancers, along with other sporadic findings. Detailed findings from animal toxicological studies are documented in Supplemental Digital Content, Table S3 (http://links.lww.com/JOM/C292).

Any Type of Cancer

Two epidemiologic cohort studies assessed the association between jet fuel exposure and incidence of cancer at any site using internal comparison groups.^33,34 D’Este et al (2008) examined overall cancer incidence (excluding nonmelanocytic skin cancer) in male former Royal Australian Air Force (RAAF) personnel who participated in the F-111 fuel tank deseal/reseal (DSRS) program, a task that involved entering fuel tanks to perform repair and maintenance procedures. Participants experienced both dermal and inhalation exposure to a variety of chemicals, including hexavalent chromium, ethylbenzene, organic solvents, and jet fuel.³³ The study compared DSRS participants to two control groups of individuals who never participated in DSRS: nontechnical personnel at the same base and technical personnel at a different base. Cancer incidence was higher among the former DSRS participants (27 cases) compared to both nontechnical personnel at the same base (incident rate ratio [IRR] for last job posting: 1.62, 95% confidence interval [CI]: 1.03–2.47) and technical personnel at a different base (IRR for last job posting: 1.60, 95% CI: 1.02–2.41). However, a nested case-control study of active-duty US Air Force (USAF) personnel found no association between occupational fuel exposure intensity and invasive cancer occurrence (7 high exposure cases) (odds ratio [OR] for high exposure vs. low exposure: 0.73, 95% CI: 0.32–1.64).³⁴ This study categorized subjects’ jet fuel exposure level based on their Air Force occupation with the highest estimated occupational fuel exposure. Those in Aircraft Fuel Systems, an occupation involving frequent inhalation and dermal exposure from fuel tank entry and contact with fuel-containing structures, were assigned to the high exposure group. The medium group included fuel storage and distribution personnel with intermittent or indirect exposure. All other occupations, considered unlikely to involve jet fuel contact, were classified as low exposure.³⁴ Sex-stratified analyses did not reveal significant associations in either high exposure males (6 cases) or females (1 case) (OR for high exposure vs low exposure, in males: 0.70, 95% CI: 0.29–1.67; in females: 1.00, 95% CI: 0.11–8.95).

Findings were also mixed in two epidemiologic cohort studies that evaluated the association between jet fuel exposure and mortality from cancer at any site using internal comparison groups.^18,33 Radican et al (2008) followed up on a cohort of civilians employed at Hill Air Force Base (AFB) between 1952 and 1956¹⁸ initially established by Spirtas et al (1991).³⁵ While trichloroethylene (TCE) inhalation was the main occupational exposure of interest, these studies also examined cancer mortality related to inhalation of other chemicals, including JP-4. Radican et al (2008) observed a significant increase in overall cancer mortality among male workers exposed to JP-4 (375 cases) compared to unexposed males (hazard ratio [HR]: 1.21, 95% CI: 1.02–1.43).¹⁸ In the RAAF cohort, D’Este et al (2008) observed a significantly lower overall cancer mortality in DSRS participants (9 cases) than in either of the comparison groups (mortality rate ratio [MRR] for last job posting, compared to nontechnical personnel at the same base: 0.35, 95% CI: 0.16–0.67; compared to technical personnel at a different base: 0.33, 95% CI: 0.15–0.63).³³ However, the authors attributed this result, in part, to survivor bias, noting that the DSRS exposed group had a lower standardized mortality rate relative to the Australian population than either of the comparison group (details presented hereinafter).

Three epidemiologic studies used standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) to assess rates of any cancer in cohorts of military personnel relative to the general population.^33,36,37 Seldén and Ahlborg (1991) followed a cohort of service members from the Swedish Armed Forces (SAF) who were exposed “normally and in any appreciable degree” to MC 77 (JP-4) or MC 25 (isopropyl nitrate, a synthetic fuel used in starter motors) between 1972 and 1974 according to administrative records.³⁶ In their reassessment of probable fuel exposures among Air Force personnel (86% of the cohort), 94.3% were considered to have been exposed to MC 77 or MC 75 (Jet A), 80% were considered to be exposed to MC 25, and 38% were believed to have been exposed to MC 55 (leaded aviation gasoline). Some individuals may have also been exposed to organic solvents, but no data on these or other potential co-exposures were available. After 9 years of follow-up, there were slightly fewer than expected, though not significantly, incident cancers (47 cases; SIR: 91, 95% CI: 66–120) and cancer deaths (24 cases; SMR: 77, 95% CI: 49–114) in male SAF service members with jet fuel exposure relative to the Swedish general population.³⁶ D’Este et al (2008) found slightly but nonsignificantly elevated incident cancers than expected in former DSRS participants (27 cases) relative to the general Australian population (SIR: 148, 95% CI: 98–216).³³ However, cancer mortality was significantly lower than expected in the former DSRS participants (9 cases) (SMR: 30, 95% CI: 14–57). In another study, the US Department of Defense examined cancer rates among current and former aircrew and ground crew from all branches of the US military, although it did not assess any specific occupational exposure.³⁷ This study reported a slightly higher incidence of cancer at any site among both aircrew (5155 cases) and ground crew (11,909 cases) than expected relative to the US population (aircrew SIR: 1.24, 95% CI: 1.21–1.27; ground crew SIR: 1.03, 95% CI: 1.01–1.05). The overall cancer mortality (aircrew: 1240 cases; ground crew: 5784 cases) was significantly lower in the military personnel than expected relative to the US population (aircrew SMR: 0.44, 95% CI: 0.41–0.46; ground crew SMR: 0.65, 95% CI: 0.63–0.66). The authors of all three of these studies speculated that lower than expected mortality cases in their cohorts may have been due to survival bias, particularly from the healthy soldier effect, a concept comparable to the healthy worker effect. This effect describes observations that military personnel tend to have decreased mortality rates than the general population, possibly due to the initial physical fitness standards required to join the military, the necessity of maintaining good physical health, and ready access to preventative healthcare during service.³⁸ As a result, comparisons between soldiers and the general population may underestimate true health risks associated with occupational exposures.

One animal toxicological study investigated the effect of jet fuel exposure on the metastasis of implanted tumor cells.³⁹ Harris et al (2007) dermally exposed female mice to JP-8 for 1 hour per day either for seven consecutive days prior to a subcutaneous implantation of B16 melanoma cells (pre-exposure) or for 1 hour on the same day as tumor implantation (concurrent exposure), with both groups continuing exposure for an additional 17 days.³⁹ Mice pre-exposed to jet fuel before tumor cell injection exhibited an 8.7-fold increase in tumor colonies, with tumor burdens ranging from a 3- to 18-fold increase compared to controls, whereas animals concurrently exposed to jet fuel experienced a slightly lower increase in tumor burden (5.6-fold) compared to controls. The authors attributed the enhanced tumor metastasis following jet fuel exposure to immunosuppressive effects, as discussed further in section 3.3.7 (KC 7: Immunosuppression).

Kidney Cancer

Three epidemiologic case-control studies evaluated the association between occupational jet fuel exposure and kidney cancer incidence.^34,40,41 Siemiatycki et al (1987) and Parent et al (2000) examined some of the same male cancer patients recruited from hospitals in Montreal, Canada, in comparison to different reference groups.^40,41 Investigators used structured interviews to gather detailed occupational histories from participants. A team of chemists and industrial hygienists translated each occupation into a list of potential exposures,⁴² drawing from a coding sheet of 275 entries, which included both “jet fuel” and “engine emissions (jet fuel)” in separate exposure categories.⁴⁰ Siemiatycki et al (1987) observed that patients with any jet fuel exposure (7 cases) had higher odds of being diagnosed with kidney cancer than unexposed patients (OR: 2.5, 95% CI: 1.1–5.4). The association was stronger after adjusting for socioeconomic covariates and restricting analyses to patients with “substantial” fuel exposure (6 cases; OR: 3.5, 95% CI: 1.5–7.6).⁴⁰ Analyses were not adjusted for exposure to other petroleum-derived liquids. No associations were observed between jet fuel and other types of cancer. Parent et al (2000) focused on renal cell carcinoma cases from the same hospital population as Siemiatycki et al (1987), using a reference group that combined some of Siemiatycki et al’s controls (cancer cases with diagnoses other than renal cell carcinoma) and additional controls randomly selected from the general population.⁴¹ The authors observed that exposure to liquid jet fuel, jet fuel emissions, and liquid aviation gasoline were highly correlated, and so they did not control for these co-exposures in the final models. Aircraft mechanics (4 cases) and males occupationally exposed to liquid jet fuel (6 cases) had higher odds of renal cell carcinoma compared to unexposed males (aircraft mechanics, OR: 2.8, 95% CI: 1.0–8.4; liquid jet fuel, OR: 3.5, 95% CI: 1.4–8.7). No association was observed between exposure to jet fuel engine emissions (4 cases) and renal cell cancer diagnosis (OR: 2.7, 95% CI: 0.9–8.1). D’Mello and Yamane (2007) observed no association between intensity of occupational jet fuel exposure and renal cell cancer incidence (2 cases) in a nested case-control study of active-duty USAF personnel (OR: 0.83, 95% CI: 0.21–3.32).³⁴

Two epidemiologic studies assessed rates of kidney cancer in military personnel relative to general populations. One study from the US Department of Defense used SIRs to assess the incidence of kidney and renal pelvic cancer in current and former aircrew and ground crew relative to the general US population.³⁷ The study reported a slightly higher than expected incidence of kidney and renal pelvic cancer in ground crew (513 cases; SIR: 1.09, 95% CI: 1.00–1.18), but not aircrew (191 cases; SIR: 0.83, 95% CI: 0.72–0.96). Seldén and Ahlborg (1991) reported no difference in rates of kidney cancer incidence in a cohort of SAF personnel (2 cases) relative to the Swedish general population (SIR: 83, 95% CI: 10–299).³⁶

Three animal toxicological studies reported elevated levels of kidney cancer in male rats following jet fuel exposure.^27,28,31 All three studies employed the same exposure paradigm: inhalation exposure to jet fuel for over 1 year, followed by a 1-year recovery period. Haun et al (1985) assessed male and female rats, male and female dogs, female mice, and male hamsters exposed to JP-10 and found that only male rats developed kidney neoplasms (renal adenoma incidence: control: 0/50; 100 ppm: 5/50).³¹ Kinkead et al (1991) exposed male and female rats and mice to JP-7 or JP-Thermally Stable (TS) and, similarly, reported an increase in kidney neoplasms in male rats exposed to JP-7 only (renal adenoma incidence: control: 0/100; 150 mg/m³: 0/100; 750 mg/m³: 4/100).²⁸ Bruner et al (1993) exposed both male and female rats and mice to JP-4 for 6 hours per day, 5 days per week, over the course of 1 year, followed by a 12-month recovery period.²⁷ Bruner et al (1993) observed what the authors reported as a “biologically significant” increase in kidney neoplasms in male rats (renal adenoma incidence: control: 0/86; 1000 mg/m³: 0/84; 5000 mg/m³: 3/86); however, no effects were noted in the kidneys of the other exposed animals.²⁷ Across all three studies, increased neoplastic kidney lesions were noted in male animals, but not in females. The authors attributed this elevated incidence of kidney tumors in male animals to α2μ-globulin nephropathy syndrome, which is unique to male rats and is not considered relevant to human health⁴³; however, levels of α2μ-globulin were not directly measured by any of the studies that reported dose-dependent increases in renal nonneoplastic lesions.

Bladder Cancer

Three epidemiologic studies provide findings on bladder cancer incidence using internal comparison groups.^34,40,44 Reed et al (2020) conducted a cross-sectional study of recently diagnosed bladder cancer patients in the United Kingdom to assess potential associations between occupational exposures and cancer phenotypes. Among patients who self-reported having ever worked with aircraft fuel, higher grade tumors (Grade 3) were more common than lower grade tumors (Grades 1 or 2) (1 case of Grade 1, 1 case of Grade 2, 7 cases of Grade 3; no comparison group). Two other case-control studies in active-duty USAF personnel and male cancer patients in Montreal observed no associations between jet fuel exposure and bladder cancer (D’Mello et al: OR: 0.70, 95% CI: 0.10–5.07; Siemiatycki et al: OR: 0.7, 95% CI: 0.3–1.8).^34,40

Two additional studies examined bladder cancer incidence and mortality in military personnel relative to general populations. A study of fuel-exposed SAF personnel (4 cases) and a study of current and former US military aircrew (175 cases) and ground crew (463 cases) found no evidence of increased risk of bladder cancer incidence (Seldén and Ahlborg SIR: 106, 95% CI: 28–271 relative to the Swedish general population; Department of Defense aircrew SIR: 0.65, 95% CI: 0.56–0.75 relative to the US general population; ground crew SIR: 0.90, 95% CI: 0.82–0.98 relative to the US general population).^36,37 There was no increase in bladder cancer mortality relative to the general US population in aircrew (26 cases) or ground crew (120 cases) occupations (aircrew SMR: 0.48, 95% CI: 0.32–0.71; ground crew SMR: 0.75, 95% CI: 0.63–0.90).³⁷ None of the identified animal toxicological studies observed adverse effects on bladder cancer.

Testicular Cancer

One epidemiologic case-control study evaluated the association between military occupation and incident testicular cancer in active-duty Royal Navy (UK) personnel, although exposure to jet fuels was not identified as the exposure of concern.⁴⁵ Ryder et al (1997) found that members of the Fleet Air Arm branch (19 cases) had significantly higher odds of testicular cancer diagnosis than members of all other service branches (OR: 1.90, 95% CI: 1.04–3.48).⁴⁵ Analyses of occupational subspecialties within the Fleet Air Arm branch identified a strong, but imprecise association between the Royal Navy Air Engineer Aircraft Handler subspecialty (6 cases) and testicular cancer (OR: 7.31, 95% CI: 1.81–29.53). The US Department of Defense reported a nonsignificantly higher incidence of testicular cancer in a cohort of current and former aircrew (196 cases) and ground crew (473 cases) than expected relative to the general population (aircrew SIR: 1.10, 95% CI: 0.95–1.27; ground crew SIR: 1.01, 95% CI: 0.92–1.11).³⁷ The study also found a significantly lower testicular cancer mortality in aircrew (3 cases), but not ground crew (38 cases), than expected relative to the general population based on SMRs (aircrew SMR: 0.25, 95% CI: 0.05–0.74; ground crew SMR: 0.83, 95% CI: 0.59–1.14). A study of fuel-exposed SAF personnel observed slightly higher, but nonsignificant, incident testicular cancers (1 case) than expected relative to the Swedish population (SIR: 110, 95% CI: 2–612).³⁶ However, as described above, the authors of both the US Department of Defense and SAF studies raised the possibility that results were biased by the healthy soldier effect.

One animal toxicological study reported an increase in testicular cancer in male rats.²⁷ Bruner et al (1993) exposed male mice and rats to JP-4 via inhalation for 1 year, followed by a 12-month recovery period.²⁷ Male rats exposed to JP-4 at high doses developed interstitial cell tumors at a higher rate than both controls and low-dose groups (interstitial cell tumor incidence: control: 71/86; 1000 mg/m³: 72/85; 5000 mg/m³: 81/95). Although this effect was not observed in male mice, the authors did note an increase in both testicular atrophy and interstitial cell hyperplasia in exposed male mice (interstitial cell hyperplasia incidence: control: 0/69; 1000 mg/m³: 0/51; 5000 mg/m³: 6/38).

Dermal Cancer

One epidemiologic cohort study assessed rates of melanoma in current and former aircrew (802 cases) and ground crew (937 cases) relative to the US general population and observed significantly higher incidence than expected in military service members (aircrew SIR: 1.87, 95% CI: 1.74–2.00; ground crew SIR: 1.09, 95% CI: 1.02–1.16).³⁷ One case report described a 22-year-old, active-duty, US Air Force Senior Airman who developed an epithelioid sarcoma on her left thumb.⁴⁶ The patient had 4 years of occupational experience fueling jet aircraft, and while she always wore required personal protective equipment, she recalled four instances that hydrazine fuel spilled over the top of her glove, contaminating her left hand. The report’s authors hypothesized that the tumor was a consequence of this dermal exposure to hydrazine fuel.

Four studies assessed dermal exposure to jet fuels in male and/or female mice.^47–50 Clark et al (1988) reported increased squamous cell carcinoma or fibrosarcoma in male and female mice dermally exposed to 25 mg/animal of both shale- and petroleum-derived Jet A and JP-4 for 3 days per week over 105 weeks (tumor incidence: shale derived; control: 1/46; JP-4: 21/42; Jet A: 12/43; petroleum derived; control: 0/46; JP-4: 9/34; Jet-A: 11/43).⁴⁷ Freeman et al (1993) exposed male mice to 37.5 μL of Jet A twice weekly for 2 years and observed a significantly higher incidence of dermal tumors in exposed animals (tumor incidence: control: 0/50; Jet A: 22/50).⁴⁸ The authors reported that animals exposed to jet fuel developed excessive irritation, prompting them to pause treatment in half of the exposed group until the irritation subsided. Mice receiving this intermittent dosing, whereby treatment was periodically suspended to allow skin irritation to resolve, did not exhibit a tumor response different from controls (tumor incidence: control: 0/50; Jet A [intermittent dosing]: 1/50). Nessel et al (1999) administered a single dermal treatment of dimethylbenzanthracene (DMBA, a known carcinogen) to male mice, followed by Jet A exposure at 28.6% v/v 7 days a week or 100% v/v 2 days a week for 1 year.⁴⁹ While control animals did not develop tumors after DMBA exposure, animals exposed to undiluted Jet A (100% v/v) developed a significantly higher tumor response compared to both diluted (28.5% v/v) and control groups (tumor incidence: control: 0/30; DMBA + Jet A (28.6% v/v): 0/30; DMBA + Jet A (100% v/v): 11/30). A National Toxicology Program (1986) study exposed male and female mice to JP-5 dermally for 5 days per week over 105 weeks and reported no significant changes in the development of dermal tumors or tumors in any other organs following exposure (tumor incidence: male control: 0/50; 250 mg/kg: 1/50; 500 mg/kg: 1/49; female control: 0/48; 250 mg/kg: 0/49; 500 mg/kg: 1/47).⁵⁰

Other Types of Cancer

Two epidemiologic studies evaluated other types of cancer in the same cohort of former civilian workers at Hill AFB. Spirtas et al (1991) followed the cohort from enrollment in 1952–1956 through 1982 and evaluated cancer mortality in the cohort relative to the population of Utah, where the base is located.³⁵ Radican et al (2008) extended follow-up through 2000, comparing cancer mortality in exposed workers compared to unexposed workers at Hill AFB.¹⁸ Over the initial follow-up period, Spirtas et al (1991) observed significantly higher mortality than expected from cancer of the buccal cavity and pharynx in female workers exposed to JP-4 (case numbers not reported; SMR: 853, 95% CI: 103–3079).³⁵ Later, Radican et al (2008) found significantly higher rates of pancreatic cancer mortality among female workers exposed to JP-4 (5 cases) compared to unexposed female workers (HR: 3.31, 95% CI: 1.01–10.84).¹⁸ Radican et al (2008) did not observe an association between jet fuel exposure and female breast cancer mortality (9 cases; HR: 1.06, 95% CI: 0.51–2.21).¹⁸ Neither study reported significant mortality from non-Hodgkin’s lymphoma (Spirtas et al: men: 5 cases, women: 1 case; Radican et al: men: 19 cases, women: 2 cases) (Spirtas et al: men: SMR: 114, 95% CI: 37–227; women SMR: 184, 95% CI: 5–1022; Radican et al: men: HR: 1.71, 95% CI: 0.74–3.95; women HR: 0.70, 95% CI: 0.16–3.15) or multiple myeloma (Spirtas et al: men: 2 cases, women: no cases; Radican et al: men: 11 cases, women: 2 cases) (Spirtas et al: men SMR: 106, 95% CI: 13–382; Radican et al: men HR: 1.29, 95% CI: 0.47–3.53; women HR: 1.98, 95% CI: 0.36–10.82).^18,35 No other cancer outcomes were reported in these studies.

The US Department of Defense report evaluated incidence and mortality rates for nine additional cancer types in current and former aircrew and ground crew relative to the general US population, with mixed findings.³⁷ Incidence of thyroid cancer was higher than expected in both aircrew (180 cases) and ground crew (369 cases) (aircrew SIR: 1.39, 95% CI: 1.20–1.61; ground crew SIR: 1.15, 95% CI: 1.04–1.27), while prostate cancer incidence was higher than expected among aircrew (1542 cases) but not among ground crew (2694 cases) (aircrew SIR: 1.16, 95% CI: 1.10–1.22; ground crew SIR: 0.95, 95% CI: 0.91–0.98). Brain and nervous system cancer incidence was also higher than expected among ground crew (340 cases) but not aircrew (122 cases) (aircrew SIR: 1.00, 95% CI: 0.83–1.19; ground crew SIR: 1.19, 95% CI: 1.06–1.32). There were fewer than expected, though not significantly, incident pancreatic cancers (aircrew: 103 cases; ground crew: 240 cases) (aircrew SIR: 0.88, 95% CI: 0.72–1.07; ground crew SIR: 0.93, 95% CI: 0.82–1.06), and non-Hodgkin lymphomas (aircrew: 298 cases; ground crew: 667 cases) (aircrew SIR: 0.99, 95% CI: 0.88–1.11; ground crew SIR: 0.97, 95% CI: 0.89–1.04). Incidences of colon and rectal (aircrew: 282 cases; ground crew: 842 cases) (aircrew SIR: 0.56, 95% CI: 0.50–0.63; ground crew SIR: 0.75, 95% CI: 0.70–0.80) and lung and bronchus cancers (aircrew: 164 cases; ground crew: 800 cases) were lower than expected in aircrew and ground relative to the general population (aircrew SIR: 0.29, 95% CI: 0.25–0.34; ground crew SIR: 0.66, 95% CI: 0.61–0.71).

Mortality from colon and rectal (aircrew: 107 cases; ground crew: 535 cases) (aircrew SMR: 0.40, 95% CI: 0.33–0.48; ground crew SMR: 0.63, 95% CI: 0.58–0.68), pancreatic (aircrew: 112 cases; ground crew: 426 cases) (aircrew SMR: 0.67, 95% CI: 0.55–0.80; ground crew SMR: 0.84, 95% CI: 0.76–0.92), prostate (aircrew: 63 cases; ground crew: 190 cases) (aircrew SMR: 0.66, 95% CI: 0.50–0.84; ground crew SMR: 0.57, 95% CI: 0.49–0.65), brain and nervous in aircrew only (aircrew: 103 cases; ground crew: 390 cases) (aircrew SMR: 0.76, 95% CI: 0.62–0.92; ground crew SMR: 0.93, 95% CI: 0.84–1.03), female breast cancers in aircrew only (aircrew: 8 cases; ground crew: 89 cases) (aircrew: SMR: 0.46, 95% CI: 0.20–0.90; ground crew SMR: 0.92, 95% CI: 0.74–1.13), and non-Hodgkin lymphoma (aircrew: 49 cases; ground crew: 250 cases) (aircrew SMR: 0.42, 95% CI: 0.31–0.56; ground crew SMR: 0.66, 95% CI: 0.58–0.75) was lower than expected in military personnel relative to the general US population. As previously noted, the study authors identified potential bias from the healthy soldier effect, which could have contributed to lower rates of cancer mortality in aircrew and ground crew compared to the general public.

Seldén and Ahlborg (1991) observed a greater number of prostate (8 cases) (SIR: 142, 95% CI: 61–280) and urogenital cancers (16 cases) (SIR: 119, 95% CI: 67–193) in SAF personnel relative to the Swedish general population, although both were nonsignificant. Fewer than expected cases of cancer were observed for some cancer types in fuel-exposed SAF personnel relative to the Swedish general population, including stomach (1 case) (SIR: 35, 95% CI: 0–193), colon (3 cases) (SIR: 89, 95% CI: 18–259), liver (1 case) (SIR: 83, 95% CI: 2–464), lung (4 cases) (SIR: 62, 95% CI: 16–157), lymphatic (3 cases) (SIR: 93, 95% CI: 19–273), or other cancers (15 cases) (SIR: 86, 95% CI: 48–141); and a greater number of cases were observed for two types of cancer: pancreatic (2 cases) (SIR: 109, 95% CI: 13–395) and leukemia (2 cases) (SIR: 112, 95% CI: 13–406).³⁶ However, results for individual types of cancer were typically based on very few cases (ie, ≤4 cases). The study also reported no deaths from lymphatic and hematopoietic cancers (0 observed deaths vs 3.7 expected). The authors identified the healthy soldier effect as a potential source of bias in study findings.

Other specific types of cancer assessed in epidemiologic studies by D’Mello and Yamane (2007) and Siemiatycki et al (1987) revealed no associations with jet fuel exposure.^34,40 In the population of active-duty USAF personnel, D’Mello and Yamane (2007) did not see any differences in incidence of leukemia (1 case; OR: 0.55, 95% CI: 0.12–2.52), multiple myeloma (1 case; OR: 1.33, 95% CI: 0.14–12.82), Hodgkin’s lymphoma (2 cases; OR: 0.44, 95% CI: 0.10–1.91), or breast cancer (2 cases; both sexes OR: 0.49, 95% CI: 0.11–2.17; females OR: 0.53, 95% CI: 0.12–2.33) between personnel in occupations with medium or high jet fuel exposure and personnel in low exposure occupations.³⁴ Siemiatycki et al (1987) did not observe an association between occupational jet fuel exposure and stomach (1 case) (OR: 0.2, 95% CI: 0.0–1.7), colon (7 cases) (OR: 2.1, 95% CI: 0.9–5.1), rectosigmoid (2 cases) (OR: 0.8, 95% CI: 0.2–3.8), rectal (4 cases) (OR: 2.1, 95% CI: 0.6–7.4), or prostate cancer (4 cases) (OR: 0.7, 95% CI: 0.2–2.1) in male cancer patients in Montreal, Canada.⁴⁰ Neither study reported an association between jet fuel exposure and incidence of lung cancer (D’Mello and Yamane: 1 exposed case, OR: 0.79, 95% CI: 0.09–7.28; Siemiatycki et al, adenocarcinoma: 2 exposed cases, OR: 1.2, 95% CI: 0.2–6.6) or non-Hodgkin’s lymphoma (D’Mello and Yamane: 4 exposed cases, OR: 1.00, 95% CI: 0.33–3.03; Siemiatycki et al: 2 exposed cases, OR: 0.7, 95% CI: 0.2–3.2).

Three animal toxicological studies identified endocrine-related cancer outcomes in male and female rats.^27,28,30 Gaworski et al (1985) exposed male and female rats and female mice to petroleum-derived or shale-derived JP-5 for 24 hours a day over a 90-day period and evaluated histopathological outcomes 21 months after exposure. In males exposed to petroleum-derived JP-5, there was an increase in pituitary adenomas (tumor incidence: control: 7/48, 150 mg/m³ 18/49, 750 mg/m³ 13/47). In females exposed to shale-derived JP-5, pituitary adenomas were also elevated (tumor incidence: control: 10/45, 150 mg/m³: 23/47, 750 mg/m³: 11/45). In addition, findings in males included higher rates of thyroid C-cell tumors in shale-derived JP-5 (tumor incidence: control: 2/50, 150 mg/m³ 13/49, 750 mg/m³ 7/50) and adrenal pheochromocytoma (tumor incidence: control: 1/50, 150 mg/m³ 0/50, 750 mg/m³ 8/47). The authors attribute increases in male adrenal pheochromocytoma to secondary effects of Ca:PO₄ imbalances caused by severe nephropathy while suggesting that all other endocrine tumors observed were typical in aged animals.³⁰ Bruner et al (1993) exposed male and female rats and mice to JP-4 for 6 hours per day, 5 days per week, for 1 year with a 1 year recovery period and observed an increase in pituitary gland adenomas/carcinomas in female rats (tumor incidence: control: 19/82; 1000 mg/m³: 31/84; 5000 mg/m³: 36/84); however, this effect was not observed in male rats or in mice.²⁷ Kinkead et al (1991) exposed male and female rats and mice to JP-7 or JP-TS, reporting an increase in thyroid C-cell adenomas in JP-TS female rats (tumor incidence: control: 0/100; 200 mg/m³: 15/100; 1000 mg/m³: 4/100).²⁸ This finding was accompanied by a dose-dependent increase in C-cell hyperplasia in females that was observed in >50% of the total animal population regardless of exposure status. The high prevalence of these nonneoplastic lesions may have contributed to, or increased the likelihood of, neoplasm development. One study identified an increase in leukemia in female rats.³¹ Haun et al (1985) exposed male and female rats to JP-10 for 6 hours a day, 5 days per week, over the course of 1 year, followed by a 12-month recovery period.³¹ The authors reported an increase in mononuclear cell leukemia in female rats (leukemia incidence: control: 2/50; 100 ppm: 11/50); this effect was not observed in male rats or in other species assessed (ie, mouse, hamster, dog).

Two studies reported elevated incidence of liver cancer in female mice.^27,30 Bruner et al (1993) exposed male and female rats and mice to JP-4 for 6 hours per day, 5 days per week, over 1 year, with a subsequent 1-year recovery period.²⁷ The exposed female mice showed a significant increase in hepatocellular adenomas compared to unexposed mice (tumor incidence: control: 2/83; 1000 mg/m³: 1/79; 5000 mg/m³: 8/80). Gaworski et al (1985) exposed female mice to petroleum- and shale-derived JP-5 noting an increase in hepatocellular adenoma in shale-derived only (tumor incidence: control: 0/93; 150 mg/m³: 1/97; 750 mg/m³: 6/95).³⁰

Several toxicological studies reported null findings, but the limited number of both animal and human studies highlights important gaps in the literature on the potential carcinogenic effects of jet fuel exposure. As noted in Supplemental Digital Content, Table S3 (http://links.lww.com/JOM/C292), of the 12 primary animal toxicological studies identified, four studies found no significant changes in neoplastic endpoints.^26,29,32,50 Secondary reviews literature discussed the lack of primary epidemiologic studies assessing the association between exposure to jet fuel and cancer.^1,4,51 Both the NRC (2003) and Richie et al (2003) suggested that further research is warranted based on the limited evidence available.^4,51

Key Characteristics of Human Carcinogens

In 2012, the International Agency for Research on Cancer (IARC) initiated an international working group to identify a systematic methodology for the identification, organization, and synthesis of mechanistic data. The KCCs were established to aid in decision-making in cancer hazard identification processes.¹⁵ Here, we briefly describe the identified mechanistic evidence in relation to the KCCs, supporting the cancer outcomes observed in humans and animals following jet fuel exposure. Findings are summarized in Supplemental Digital Content, Table S1 (http://links.lww.com/JOM/C240), while detailed findings from mechanistic studies are presented in Supplemental Digital Content, Table S4 (http://links.lww.com/JOM/C293).

Key Characteristic #1: Is Electrophilic or Can Be Metabolically Activated to Be Electrophilic

The first characteristic of carcinogenicity requires compounds to be either electrophilic or become metabolically activated to become electrophilic. Biomarkers of electrophilicity may include the onset of DNA or protein adducts.⁵² The literature search did not identify any studies specifically investigating the electrophilicity of jet fuels or their potential to form DNA adducts. As a result, no direct evidence was available to assess this characteristic in relation to jet fuel exposure.

Key Characteristic #2: Is Genotoxic

Genotoxicity, or the ability of a substance to damage the DNA in a cell, can lead to a myriad of dysfunctions within a cell. Biomarkers of genotoxicity may present as mutations, single nucleotide variants, structural chromosomal alterations, DNA strand breaks, or aneugenicity.⁵² Of the 15 studies identified that evaluated the potential genotoxic effects of jet fuel exposure, four in vitro studies reported potential to induce DNA damage, while no studies reported mutagenic or clastogenic effects. Two studies reported an increased incidence of DNA damage, via comet assays, in a rat hepatocellular carcinoma cell line (H4IIE) exposed to JP-8⁵³ and human peripheral blood lymphocytes exposed to either JP-5, JP-8, or JP-8 + 100.⁵⁴ Another study noted membrane blebbing and DNA fragmentation in human histiocytic lymphoma (U-937) and rat lung epithelial cells (RLE-6TN) after JP-8 exposure.⁵⁵ Two studies reported positive results regarding the ability for JP-4⁵⁶ and JP-8⁵⁷ to induce unscheduled DNA synthesis in human embryonic lung cells; however, the authors noted that the findings were not necessarily mutagenic in nature.

The remaining 12 studies evaluating the genotoxic potential of jet fuels either in vitro or in vivo reported no significant differences between jet fuel-exposed groups and unexposed controls. In these studies, genotoxic evaluations were conducted using bone marrow, blood, or peripheral lymphocyte samples across male and female F344 rats exposed via inhalation,^58–62 C3H/HeNCr mice exposed via dermal or inhalation routes,^63–65 occupationally exposed male and female service members,^66,67 and bacterial strains exposed in vitro.^61,62,68,69 Furthermore, these genotoxicity assays were conducted following exposure to JP-8,^{63,64,66–68} Jet A,^63,64 and synthetic jet fuels,⁶⁹ including alcohol-to-jet synthetic kerosene with aromatics with and without JP-8,^58–61,68 and hydroprocessed esters and fatty acids (HEFA) fuels HEFA-T, HEFA-C, and HEFA-F.⁶²

Key Characteristic #3: Alters DNA Repair or Causes Genomic Instability

The third characteristic of carcinogenicity requires compounds to alter DNA repair pathways or cause genomic instability. The literature search did not identify any studies specifically investigating alteration of DNA repair mechanisms. As a result, no direct evidence was available to assess this characteristic for jet fuel.

Key Characteristic #4: Induces Epigenetic Alterations

The ability of a substance to induce epigenetic alterations, or any modification that changes gene expression or chromatin arrangement without altering DNA sequence, has been identified as a characteristic of carcinogenicity. Biomarkers of epigenetic alterations include DNA methylation, histone modifications, chromatin remodeling, or noncoding RNA regulation that can modify the transcription of DNA or translation of mRNA.⁵² Epigenetic markers may serve as mediatory of cancer etiology and progression, and downstream effects of epigenetic modifications may depend on the location in the genome that is impacted (eg, promotor region, oncogenes, tumor suppressor genes, DNA repair genes). Dysregulation of epigenetic mechanisms, therefore, may be a secondary mechanism of carcinogenesis, although studies demonstrating epigenetic modifications by jet fuel exposures are of note given the evolving generation of mechanistic data for this characteristic of carcinogenicity.

All six studies that evaluated the epigenetic effects of jet fuel exposure reported positive results. Of these, four studies reported increased incidence of transgenerational sperm epimutations or DNA methylated regions in male rats exposed to JP-8, leading to altered expression of genes associated with health outcomes, including kidney disease, obesity, aberrant puberty pathology, and several other pathologies.^70–73 Given the heritable susceptibility to cancer, it is of note that epigenetic alterations in sperm, induced by jet fuel exposures, may be passed to later generations. Mauzy et al (2022) reported increased miRNA alterations in three brain regions following jet fuel inhalation in male and female rats.⁷⁴ The locations with the highest levels of differential miRNA varied by jet fuel type, with JP-8–induced alterations occurring most in the cerebellum, Jet A in the cerebellum and hippocampus, JP-5 in the prefrontal cortex, and Fischer Tropsch in the prefrontal cortex. Mattie et al (2024) reported significantly altered miRNAs within blood and urine samples from military personnel exposed to Jet A1. The aberrant miRNA expressions identified regulate cellular responses to stress from chemical exposure and have been noted in cancer and other systemic diseases.⁷⁵

Key Characteristic #5: Induces Oxidative Stress

The imbalance and eventual overproduction of reactive oxygen species (ROS) has been identified as a characteristic of carcinogenicity. ROS are generated through normal cellular metabolic activities with both constitutive and inducible processes at play inside the cell (eg, enzymatic antioxidants, nonenzymatic ROS scavengers, transition metal ion sequestrators). These processes maintain homeostatic balance by protecting DNA, proteins, and other important cellular macromolecules from oxidative damage.⁷⁶ Uncontrolled oxidative stress can lead to DNA damage and mutations, transcription factor activation or inactivation, and other cell signaling perturbations that ultimately lead to carcinogenesis.⁷⁷ Biomarkers of oxidative stress may include, but are not limited to, cyclooxygenase-2 (COX-2) activation, modified antioxidant responses, poly(ADP-ribose) polymerase-1 (PARP-1) activation, or nuclear factor kappa B (NF-κβ) activation.

Fourteen studies were identified that evaluated oxidative stress due to JP-8 (n = 12), Jet A (n = 2), synthetic jet fuels (S-8; n = 2), and HEFA (n = 1). Five of these 14 studies reported increases in intracellular ROS through both direct measurement (eg, levels of peroxynitrite, nitric oxide) and oxidation product generation.^78–82 In addition, Espinoza et al (2007) and Ramos et al (2008) identified complementary increases in various enzymes responsible for generating ROS, including inducible nitric oxide synthase and COX-2.^78,82 Levels of known enzymatic antioxidants and the substrates they conjugate to detoxify ROS, such as glutathione-S-transferases and their substrate glutathione, were also assessed across multiple model systems in seven studies.^{78–80,83–86} These studies reported modification to antioxidant responses, identifying both increased^78,79,83,86 and decreased^80,84,85 responses. Levels of other key enzymatic antioxidants like superoxide dismutase, catalase, and glutathione peroxidase were evaluated following exposure to JP-8 in two studies.^66,78 Levels of plasma glutathione peroxidase and erythrocytes collected from human blood were largely unchanged,⁶⁶ whereas superoxide dismutase was decreased and catalase increased in a rat alveolar macrophage cell line model⁷⁸ following jet fuel exposure.

Increases in heme oxygenase 1 (HO-1), an oxidative, stress-inducible, isoform of the heme oxygenase protein family responsible for redox homeostasis and a canonical marker of oxidative stress,⁸⁷ were observed in rat liver tissue and human bronchial epithelial cells (BEAS-2B) following exposure to JP-8, Jet A, and HEFA.^88,89 Expression of nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1, another important mediator of redox homeostasis, can be induced by oxidative stress through similar signaling pathways as HO-1.⁹⁰ The study reported nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1 expression was unchanged despite observed increases in HO-1 expression.⁸⁹ In addition, one study interpreted increased blood levels of apolipoprotein A-IV, a lipid-binding protein with known antioxidant properties,⁹¹ in rats exposed to JP-8 as a potential marker of oxidative stress.⁹²

Four studies evaluated NF-κB and PARP-1 signaling, alongside these other established oxidative stress endpoints, in relation to JP-8^78–80,82 or synthetic jet fuels.⁸² These studies reported activation of NF-κB or PARP-1 in response to JP-8 exposure in rat lung macrophages,⁷⁹ rat lung epithelial cells,^78–80 and female C3H/HeNCr mice⁸²; however, synthetic jet fuel exposure did not significantly activate NF-κB expression.⁸² In addition, a fifth study reported a reduction in IĸBα (a known NF-κB inhibitor) in the liver and kidneys of male Long Evans rats.⁸⁸ Although NF-κB is considered a master regulator of inflammatory response, downstream signaling leads to the expression of ROS-generating enzymes like inducible nitric oxide synthase and COX-2 that contribute to oxidative stress.⁹³

Of the 12 studies that evaluated oxidative stress endpoints following exposure to JP-8, the majority (11 studies) found that JP-8 exposure elicited significant changes in oxidative stress endpoints.^{78–86,88,92} Similarly, the one study that assessed exposure to Jet A found adverse effects in at least one endpoint.⁸⁹

Key Characteristic #6: Induces Chronic Inflammation

Induction of chronic inflammation is characterized by increases in pro-inflammatory cytokines, including interleukins (ILs), chemokines, interferons, or tumor necrosis factors.⁵² Chronic inflammation has been associated with several forms of cancer, and it is hypothesized that continuously upregulated inflammation may play a role in tumor development. Oxidative stress and immune response are biologically related to inflammation and inflammatory response; thus, an activator of one pathway may induce another or lead to continual feedback further exacerbating each pathway. Biomarkers of this characteristic may include activation of pro-inflammatory cytokines such as IL-1α, IL-1β, tumor necrosis factor-alpha (TNF-α), IL-8, or IL-6.

This systematic review identified 27 studies that evaluated associations between jet fuel exposure and an inflammatory response. Of the studies that reported evidence of an inflammatory response, all of the studies included data for JP-8 (n = 27), and some studies also included Jet A (n = 5), JP-5 (n = 1), or synthetic fuel (n = 2) exposures. Exposure scenarios were primarily in vivo (n = 15) and/or in vitro (n = 11). Most studies reported an inflammatory response in dermal (n = 19) or respiratory (n = 7) endpoints, but assessments of renal (n = 1), cardiovascular (n = 1), and hepatic (n = 1) outcomes were also addressed.

A majority of the 27 studies reported an inflammatory response in either dermally exposed animals (n = 12) and/or in vitro assays of human and animal epithelial cells (n = 8). These studies primarily focused on elevated levels of TNF-α, a master regulator of inflammation, and other proinflammatory cytokines, including IL-1α, IL-1β, IL-6, and IL-8. Five studies assessed levels of TNF-α in mice, rats, or in vitro models, four of which reported significantly elevated levels,^94–97 while the fifth reported elevated levels in mice that did not reach statistical significance.⁹⁸ In addition, 23 studies assessing pro-inflammatory cytokine responses predominantly reported increases in protein expression,^{79,82,88,94–113} while one study reported mixed results.¹¹⁴ In a dermal study conducted in hairless rats exposed to JP-8 or JP-8 + 100, TNF-α was elevated in skin, and IL-1α was elevated in blood 24 hours after exposure.⁹⁷ This study also evaluated exposure in human keratinocytes in vitro and reported similar findings at 24 or 48 hours after exposure. Allen et al (2000) also reported elevated levels of TNF-α peaking at 4 hours in epidermal keratinocytes after exposure to Jet A, JP-8, and JP-8 + 100.⁹⁶ This increase of TNF-α correlated to an increase in IL-8. Similarly, Inman et al (2008) reported elevated levels of IL-8 and IL-1β up to 24 hours after exposure to JP-8 and S-8, which was suppressed upon the addition of the inflammatory inhibitor substance P.¹⁰⁴ The authors also noted that the inflammatory response from S-8 was significantly lower than that of the JP-8 exposure.

Seven studies evaluated the inflammatory response in animals exposed via inhalation^114–117 or respiratory system-derived cell lines^79,106,108 after jet fuel exposure. Three studies identified increases in lung inflammation in rats and mice following exposure to jet fuels by inhalation,^115–117 while one study reported no effect in rats.¹¹⁴ Pfaff et al (1996) assessed the inflammatory response in rats exposed to JP-8 via inhalation for up to 56 days and observed a dose- and time-dependent decrease in the anti-inflammatory substance P marker.¹¹⁵ An inhalation study in mice reported an increase in the inflammatory marker leukotriene B4 and substance P on day 7 of exposure, but the authors attributed this to a modification in enzymatic degradation.¹¹⁷ Wang et al (2001) measured TNF-α levels in bronchiolar lavage fluid after inhalation of JP-8 in adolescent and adult mice when compared to their age-matched controls.¹¹⁶ The authors noted an age-related response that implicates an overreactive inflammatory response in adults when compared to younger animals. In contrast, Rohan et al (2018) assessed the effects of inhalation to JP-8, JP-5, Jet A, and synthetic Fischer Tropsch exposure in rats for 7 days and found no significant changes to eight different inflammatory cytokines in plasma.¹¹⁴ Three in vitro studies using alveolar epithelial cells observed evidence of increased inflammation after JP-8 exposure.^79,106,108 Espinoza et al (2006) reported TNF-α, NF-ĸB, PARP-1, IL-8, and IL-6 activation in alveolar type II endothelial cells exposed to JP-8.⁷⁹ Furthermore, Sun et al (2007) reported an increase in IL-1α and IL-1β in alveolar macrophages alone and co-cultured with type II epithelial cells in response to JP-8 exposure, but this effect was lost when cells were treated to substance P.¹⁰⁸ Wang et al (2002) also reported concentration-dependent increases in inflammatory cytokines IL-1β, IL-6, and TNF-α in response to JP-8 exposure in separate cultures of rat type II pneumocytes and alveolar macrophages; however, when cell lines were co-cultured, cytokine expression was significantly attenuated, suggesting that communication between the cell types is imperative to reducing an inflammatory response.¹⁰⁶ Overall, the available mechanistic evidence indicates that jet fuel exposure is linked to the induction of inflammatory responses.

Key Characteristic #7: Immunosuppression

Immunosuppression is a reduction in the immune system’s capacity to respond to foreign antigens, including tumor-specific antigens.⁵² Immunosuppressive agents do not directly induce cell transformation but reduce the immune system’s capability to respond to cell transformation through other mechanisms (ie, genotoxicity). A myriad of biomarkers for immunosuppression exist and include, but are not limited to, delayed hypersensitivity, prostaglandin E2 (PGE2) release, or the reduced proliferative capacity of immune cells such as T- or B-cells. Of the 27 studies identified as containing immune-related mechanistic data in the systematic review, 19 studies reported evidence of immunosuppression after jet fuel exposure. These studies primarily assessed responses to JP-8 exposure (n = 25), with fewer focusing on exposure to either Jet A (n = 4) or S-8 (n = 1).or S-8 (n = 1).

Several studies that reported immunosuppression outcomes in response to jet fuel exposure in mouse skin or spleen also noted a significant modification in COX-2^72,82,118 or PGE2.^{82,99,116,119,120} PGE2 stimulates the production of the immune regulator IL-10, which was also increased following jet fuel exposure.^98,120,121 Altering this pathway through the use of an antagonist, such as a COX-2 inhibitor, diminished the immunosuppressive effects of jet fuels.^119–122 Prolonged upregulation of PGE2 has been implicated in the reduction of the proliferative response of T- and B-cells, a critical component of the immune response that is largely dependent on the growth factor IL-2, which is downregulated in the presence of elevated PGE2 levels.¹²³ Thus, reduced proliferation of T- and B-cells is mediated by IL-2 in response to PGE2. In general, jet fuel exposure via inhalation and dermal exposure inhibited the proliferative capacity of T- and B-cells in the spleen or thymus of mice.^{120–122,124–130}

Platelet or plaque formations occur in areas of immune activity, where macrophages, T-cells, and B-cells interact to trigger a complex adaptive immune and inflammatory response. Three studies that assessed plaque formation in the spleens of mice exposed orally to JP-8 for a period of 7–14 days identified significant, dose-dependent reductions in plaque formation,^124,131,132 while one study reported no effect in rats in response to Jet A.¹³³ One study modified the levels of platelet activating factor in mouse keratinocytes and observed a reversal of immunosuppressive outcomes related to either JP-8 or Jet A exposure.⁹⁹

Six studies reported that animals exposed to jet fuels experienced suppressed secondary immune reactions via delayed hypersensitivity (ie, dose-dependent reduction in swelling of the ear or foot pad) following repeated immune challenge, indicating that jet fuel exposures suppressed the inflammatory response in these animals.^99,118–122 For instance, Ramos et al (2002) demonstrated that the elicitation of delayed-type hypersensitivity and immunological memory in mice were suppressed in a dose-dependent manner, with increasing concentrations of JP-8 or Jet-A applied to the skin. One study assessing JP-8 exposure via inhalation in mice for 7 days reported a decrease in N-acetyl-β-D-glucosaminidase, causing a reduction in macrophage activity.¹³⁴ Conversely, several studies failed to identify immunosuppressive effects in animals after inhalation,^{115,117,133,135–137} oral,¹³⁸ or dermal exposure¹³⁹ to JP-8 or Jet A. Overall, the available evidence demonstrates that jet fuel exposure can alter and impair immune function.

Key Characteristic #8: Modulates Receptor-Mediated Effects

The ability for a compound to act as a ligand via nuclear receptors is a defining characteristic of carcinogens. A characteristic biomarker for this KCC is the altered expression of the aryl hydrocarbon receptor (AhR). Modification to AhR expression can lead to immunosuppression in addition to effects on cell proliferation and survival.⁵² Two studies evaluated whether jet fuel exposure in lungs would alter AhR expression.^89,131 Gualtieri et al (2022) reported no significant differences in AhR or CYP1B1 expression in BEAS-2B lung cells exposed to Jet A1.⁸⁹ Similarly, Dudley et al (2001) reported no alterations in AhR and CYP1A1 expression in mouse lungs exposed to JP-8 via oral gavage.¹³¹ Furthermore, JP-8 exposure did not alter AhR or CYP1A1 expression in mouse livers in response to the oral gavage exposure, or a liver hepatoma cell line exposed in vitro.¹³¹

Key Characteristic #9: Causes Immortalization

The ninth characteristic of carcinogenicity requires compounds to induce cellular immortalization. Characteristic biomarkers for cell immortalization include telomerase activity and alterations in cellular senescence markers. This literature search did not identify any studies specifically investigating immortalization of cells. As a result, no direct evidence was available to assess this characteristic for jet fuel.

Key Characteristic #10: Alters Cell Proliferation, Cell Death, or Nutrient Supply

The tenth key characteristic of carcinogenicity relates to the ability of an agent to alter cellular replication or cell cycle control processes. Cancer cells escape normal growth patterns and evade apoptosis, continuing to replicate via mechanisms of either decreased cell death or increased cell proliferation.⁵² Biomarkers of this key characteristic of carcinogenicity include evaded or reduced apoptosis, angiogenesis, or cellular proliferation and hyperplasia. Primarily, studies that investigated the impacts of jet fuel exposure on cell growth evaluated the cytotoxic potential of jet fuels via cell viability assays in vitro, with mixed results indicating either no change in cell viability or increased cell death. Evidence that jet fuels are cytotoxic to cells largely come from in vitro assays, whereby increased cytotoxicity following JP-8 exposure has been reported in rat alveolar cells (RLE-6TN)^80,140; rat hepatoma cells (H4IIE)¹⁴¹; rat glioma (NG108-15)¹⁴¹; rat hippocampal cells¹⁴¹; human bronchial epithelial cells (BEAS-2B)¹⁴²; or human epidermal keratinocytes.^{97,104,143–145} Multiple studies have also reported that jet fuel exposure does not alter cell viability in rat alveolar cells (RLE-6TN and NR833)¹⁰⁸ or BEAS-2B cells.⁸⁹ In addition, studies assessing jet fuel exposure to mouse auditory cells lines did not find a reduction in cell death (VOT-N33, VOT-E36, HEI-OC1).⁸⁶ Therefore, the available evidence does not support the potential for jet fuel exposure to increase cell proliferation or decrease cell death.

Weight of Evidence for Carcinogenicity

Summary of Evidence

The carcinogenic potential of jet fuel has been documented in both epidemiologic and animal toxicological studies. Epidemiological evidence is primarily based on the incidence of kidney cancer reported by one medium confidence epidemiological study. Jet fuel exposure has been adversely associated with other cancer types in humans, including bladder and testicular cancer, and overall cancer incidence and mortality, although the evidence for these is generally limited to low confidence studies. Findings were equivocal for other types of cancer (eg, lung cancer, female breast cancer, multiple myeloma, and non-Hodgkin’s lymphoma), including nonsignificant associations and mixed results within and across studies.

The evidence of carcinogenicity in animal models includes one high confidence, nine low confidence, and two uninformative studies that assessed effects of jet fuels administered via inhalation, dermal, and injection exposure routes. Four studies reported on dermal jet fuel exposure (one high confidence and three low confidence) causing skin irritation and necrotic lesions. Only the three low confidence studies reported necrotic lesions that progressed into neoplasms, with continuous dosing significantly increasing tumor incidence. Three low confidence studies identified increases in kidney tumors in male rats; however, these were attributed to α2-μ-globulin nephropathy, a species-specific condition with unclear relevance to humans. In addition, other low confidence studies reported inconsistent findings, including necrotic lesions in multiple organs (liver, testis, pituitary gland, thyroid, and mammary gland), leukemia, and increased tumor metastasis following jet fuel exposure.

Evidence From Epidemiologic Studies

Evidence of associations between jet fuel exposures and kidney cancer in humans comes from three studies. Two case-control studies (one medium confidence and one low confidence) in male cancer patients in Montreal reported adverse associations between occupational exposure to jet fuel and kidney cancer and renal cell carcinoma.^40,41 Siemiatycki et al (1987) evaluated multiple cancer types found a significant relationship between both “any” or “substantial” jet fuel exposure and kidney cancer.⁴⁰ Parent et al (2000) further investigated renal cell carcinoma in a subset of the original cohort’s kidney cancer cases, comparing them with a control group incorporating population-based controls in addition to the hospital-based controls.⁴¹ The study reported significantly higher odds of renal cell carcinoma in male aircraft mechanics and males exposed to liquid jet fuel compared to unexposed males. A low confidence cohort study of US military aircrew and ground crew also reported slightly higher than expected incidence of kidney and renal pelvic cancer among ground crew, but not aircrew, relative to the general US population.³⁷ Although all three studies were limited by a lack of quantitative exposure assessment, taken together they suggest a potential link between occupational jet fuel exposures and elevated risks of kidney cancers.

One low confidence study reported an increased rate of prostate and urogenital cancers in SAF personnel relative to the Swedish population.³⁶ The rates of kidney (2 cases) and bladder cancer (3 cases) were not elevated in this study population, but results for these individual cancer types were based on a small number of cases. Analyses of all urogenital cancers combined provided greater precision and suggested an effect within the urogenital organ system, including the kidney and bladder. Another study of cancer patients provided evidence of carcinogenicity in the bladder in humans, including a higher prevalence of high-grade than lower grade cancers in patients who reported ever working with aircraft fuel.⁴⁴ The finding suggests that jet fuels might contribute to the development of more aggressive malignancies; however, the evidence comes from one low confidence study with a small number of bladder cancer cases.

Several low confidence cohort studies have investigated the association between jet fuel exposure and overall incidence and mortality from cancer at any site. D’Este et al (2008) observed an elevated incidence of cancer in former RAAF personnel who entered airplane fuel tanks frequently, and for sustained periods, compared to former service members without similar fuel tank entry experience.³³ A cohort of current and former US military aircrew and ground crew was also observed to have higher incidence and mortality from any type of cancer compared to the general population, although this was not attributed by the authors to any specific occupational exposure.³⁷ Radican et al (2008) observed higher rates of all-cause cancer mortality in men exposed to JP-4 at Hill AFB compared to their unexposed colleagues.¹⁸

Evidence From Animal Toxicological Studies

Evidence for nonmelanocytic skin cancer arises from three studies that examined dermal exposure to jet fuel in animals.^47–49 In these studies, animals were exposed to jet fuel over periods ranging from one to 2 years, with application frequencies of two to seven times per week. Each study reported that animals exposed to jet fuel developed skin irritation, necrotic lesions, and hyperplasia before progressing to neoplastic lesions. This evidence was further corroborated by mechanistic data related to KC 6 (Induces Chronic Inflammation), which indicated increased inflammation in nearly all studies assessing this endpoint. Notably, Freeman et al (1993) utilized two dosing regimens: a continuous dosing protocol over 2 years and an intermittent dosing protocol, which paused treatment when 20% or more of the cohort exhibited severe inflammation and resumed once inflammation subsided.⁴⁸ Neoplastic incidence in animals undergoing uninterrupted treatment was significantly higher than controls, whereas animals receiving intermittent dosing exhibited minimal neoplastic incidence relative to controls. These data collectively suggest that dermal exposure to jet fuel elicits an inflammatory response, which, if prolonged, may lead to neoplastic lesions.

Evidence for increased cancer risk was assessed in two animal toxicological studies that combined a tumor initiator with jet fuel exposure.^39,49 Harris et al (2007) subcutaneously injected B16 melanoma tumor cells into animals following a week of inhalation exposure to jet fuel.³⁹ The authors reported a significant increase in tumor burden and metastasis associated with prior jet fuel exposure, likely due to observed immunosuppressive effects. This finding aligns with mechanistic data related to KC 7 (Is Immunosuppressive) that indicates jet fuel acts as an immunosuppressive agent, reducing immune response and enabling tumor cells to evade the body’s defenses, thereby, promoting translocation to other body regions. Nessel et al (1999) applied jet fuel dermally following a single treatment with DMBA, a potent carcinogen.⁴⁹ The authors noted a significant increase in tumor incidence in animals exposed to jet fuel, accompanied by heightened inflammation. They suggested that tumor development may result from repeated dermal irritation, and when this irritation is mitigated, tumor incidence declines. Together, these studies suggest that the inflammatory and immunosuppressive responses induced by jet fuel may create a favorable environment for tumor growth.^39,49

Three studies in male rats support a link between jet fuel exposure and an increased incidence of kidney cancer.^27,28,31 In these studies, several animal species were exposed to various jet fuels via inhalation for 6 hours per day, 5 days per week, for over 1 year, followed by a 1-year recovery period. However, neoplastic lesion incidence rates were observed only in male rats. The authors of each study attributed the increase in neoplasms to elevated levels of α2μ-globulin nephropathy syndrome, a condition unique to male rats. As noted in Kotulkar et al (2025), in male rats, this protein promotes hyaline droplet formation and cytotoxic responses, leading to nephropathy.¹⁴⁶ EPA has also noted that humans lack proteins from the lipocalin superfamily, of which α2μ-globulin is a part, and suggest that reactions via this pathway are not expected to occur in humans.¹⁴⁷ Although authors attributed their findings to α2μ-globulin nephropathy syndrome, it is important to note that none of the available studies directly measured protein levels to confirm this mechanism. Consequently, the human relevance of these kidney tumors induced through the α2μ-globulin pathway remains uncertain.

Cancer Classification

A review of the weight of evidence in accordance with the Guidelines for Carcinogen Risk Assessment resulted in a determination that there was suggestive evidence of carcinogenic potential for jet fuel, as “a concern for potential carcinogenic effects in humans is raised, but the data are judged not sufficient for a stronger conclusion.”¹¹ This determination is based on evidence for kidney cancer in humans and dermal cancer in animals, and mechanistic evidence of oxidative stress, inflammation, and immunosuppression after exposure to jet fuel.

The Guidelines provide examples of data that may support the suggestive evidence of carcinogenic potential descriptor, and available jet fuel data are consistent with the following factors: “1) A small, and possibly not statistically significant, increase in tumor incidence observed in a single animal or human study that does not reach the weight of evidence for the descriptor ‘Likely to Be Carcinogenic to Humans.’ The study generally would not be contradicted by other studies of equal quality in the same population group or experimental system; 2) Evidence of a positive response in a study whose power, design, or conduct limits the ability to draw a confident conclusion (but does not make the study fatally flawed), but where the carcinogenic potential is strengthened by other lines of evidence (such as structure-activity relationships); or 3) A statistically significant increase at one dose only, but no significant response at the other doses and no overall trend.”¹¹ Consistent with these criteria, the available epidemiologic evidence suggests that jet fuel exposure may result in carcinogenicity in humans. Supporting evidence from animal toxicological studies indicates that jet fuel has carcinogenic potential in one animal model for multiple sites and both sexes. Table 1 presents specific details on how jet fuel exposure aligns with the examples supporting the suggestive evidence of carcinogenic potential descriptor in the Guidelines for Carcinogen Risk Assessment.¹¹

TABLE 1.

Comparison of Jet Fuels Literature With the Suggestive Evidence of Carcinogenic Potential Cancer Descriptor as Outlined in the Guidelines for Carcinogen Risk Assessment (US EPA, 2005^a)

Suggestive Evidence of Carcinogenic Potential
“A small, and possibly not statistically significant, increase in tumor incidence observed in a single animal or human study that does not reach the weight of evidence for the descriptor “likely to be carcinogenic to humans.” The study generally would not be contradicted by other studies of equal quality in the same population group or experimental system.” (US EPA, 2005)a	Jet fuel data are consistent with the description. Epidemiologic evidence supports a plausible association between jet fuel and renal cancer. Several low confidence animal toxicological studies found correlations between cancer and dermal exposure of jet fuel.
“A small increase in a tumor with a high background rate in that sex and strain, when there is some but insufficient evidence that the observed tumors may be due to intrinsic factors that cause background tumors and not due to the agent being assessed. (When there is a high background rate of a specific tumor in animals of a particular sex and strain, then there may be biological factors operating independently of the agent being assessed that could be responsible for the development of the observed tumors.) In this case, the reasons for determining that the tumors are not due to the agent are explained.” (US EPA, 2005)a	This description is not applicable to jet fuel.
“Evidence of a positive response in a study whose power, design, or conduct limits the ability to draw a confident conclusion (but does not make the study fatally flawed), but where the carcinogenic potential is strengthened by other lines of evidence (such as structure-activity relationships).” (US EPA, 2005)a	Jet fuel data are consistent with the description. Several low confidence cancer studies are supported by mechanistic data indicating that jet fuel is associated with events generally known to be associated with tumor formation such as inducing oxidative stress, chronic inflammation, and immunosuppression.
“A statistically significant increase at one dose only, but no significant response at the other doses and no overall trend.” (US EPA, 2005)a	Jet fuel data are consistent with the description. Malignant lymphomas were identified in female mice exposed to chronic low (but not high) dose (NTP, 1997).

Bold emphasis is applied as intended.

^aUnites States Environmental Protection Agency. Guidelines for Carcinogen Risk Assessment. 2005. https://www.epa.gov/sites/default/files/2013-09/documents/cancer_guidelines_final_3-25-05.pdf.

Epidemiologic findings were inconsistent across cancer types; however, the evidence was suggestive of a potential link between jet fuel exposure and kidney cancer.^40,41 One medium confidence case-control study of cancer patients in Montreal reported a significant increase in renal cell carcinoma among men with a history of occupational exposure to jet fuel.⁴¹ Evidence for other cancers is confined to low confidence epidemiologic studies that were limited by methodological issues, including selection biases, imprecise exposure assessment, residual confounding, and inadequate sensitivity. The lack of consistency in the specific cancer types assessed across epidemiologic studies precludes a more definitive determination for any specific type of cancer in humans; however, the variety of mechanistic changes observed (eg, oxidative stress, increases in inflammation, immunosuppression) may help explain the variability in tumor types reported.

Several low confidence animal studies that exposed rats to jet fuel via inhalation reported increases in renal neoplastic lesions.^27,28,31 However, the authors determined that the increases in renal toxicity and neoplastic lesions are likely attributed to α2μ-globulin nephropathy syndrome, which is unique to male rats. It is unclear if this effect in male rats could be related to any effect seen in humans.

Several animal toxicological studies also demonstrated exacerbated tumorigenesis following jet fuel exposure. Harris et al (2007) reported that prior jet fuel exposure significantly increased the ability of an intravenously injected melanoma cell line to metastasize.³⁹ Similarly, Nessel et al (1999) reported increased dermal tumorigenesis with repeated jet fuel exposure after a single exposure to a known potent carcinogen, DMBA, which failed to produce growth of tumors in control animals.⁴⁹ These findings in animal models are consistent with those from one low confidence human study, which reported a high proportion of high-grade tumors among patients recently diagnosed with bladder cancer who reported ever having worked with aircraft fuel.⁴⁴ The ability of jet fuels to exacerbate tumorigenesis is potentially linked to immunosuppressive actions. Mechanistic evidence related to KC 7 (Is Immunosuppressive) supports the ability for jet fuel exposure to reduce the immune system’s response to foreign antigens, namely, through the reduction of mitogenesis and platelet formation, attributed to increases in inflammatory mediators (ie, IL-10, COX-2, NF-κB, PGE2).

Several low confidence chronic exposure studies of male and female mice dermally exposed to jet fuel reported that prolonged exposure resulted in skin inflammation that led to either an increase in neoplastic lesions^47,48 or exacerbation of a neoplastic lesion response after a single exposure to DMBA.⁴⁹ The only high confidence study that assessed neoplastic lesions after chronic dermal jet fuel exposure reported minimal incidences of squamous cell papilloma/carcinoma.⁵⁰ These neoplastic findings are mechanistically supported by findings pertaining to KC 6 (Induces Chronic Inflammation), as many of these studies reported an exacerbated inflammatory response in dermally exposed animals. Freeman et al (1993) split the exposure group when inflammation at the application site became severe, pausing exposure on one group until the irritation subsided before restarting.⁴⁸ The continuous exposure group exhibited a significant increase in dermal neoplastic lesions, while the group with intermittent exposure exhibited almost no tumor growth.

DISCUSSION

This systematic literature review determined that there was suggestive evidence of carcinogenic potential for jet fuel as “a concern for potential carcinogenic effects in humans is raised, but the data are judged not sufficient for a stronger conclusion.”¹¹ This determination was based on evidence of kidney cancers in men occupationally exposed to jet fuel,^40,41 and skin cancer following dermal exposure to jet fuel in animal toxicological studies.^47–49 The determination is also supported by potential modes of action from the mechanistic evidence: increases in chronic inflammation (KC 6)^{88,94–98,100–105,107,110,113} and in immunosuppression (KC 7)^{82,98,99,102,118,119,121,122,148,149} in the skin following dermal exposure to jet fuel.

The present determination of suggestive evidence of carcinogenic potential for jet fuels represents a stronger conclusion than previous conclusions from authoritative reviews. The weight of evidence approach used for this review closely aligns with IARC’s method of synthesizing multiple evidence streams to reach a determination.¹⁵⁰ The most recent IARC monograph on jet fuel was published in 1989 and included only two epidemiologic studies and one animal toxicological study, which were also included in the current review.¹⁵⁰ Based on “inadequate evidence” for carcinogenicity in humans or experimental animals, IARC’s evaluation of jet fuel was “not classifiable as to its carcinogenicity to humans.” This review adds eight epidemiologic studies, 10 animal studies, and an extensive review of mechanistic evidence of carcinogenicity (IARC began incorporating KCCs into its monographs in 2015),¹⁵¹ supporting a stronger conclusion of “suggestive evidence.” The weight of evidence method also extends beyond IARC’s approach by integrating results and identifying specific gaps in the literature that could shift conclusions if comprehensively addressed. Since IARC’s 1989 assessment, ATSDR has published toxicological profiles on JP-4 and JP-7 and JP-5, JP-8, and Jet A,^8,9 but these reports serve to summarize rather than evaluate health effects, and their distinctions between different jet fuels and exposure settings limit broader conclusions. In addition, the NRC reported on the potential carcinogenicity of JP-8 in 2003.⁴ Compared with NRC, this review incorporates eight more epidemiologic studies, strengthening hazard characterization. Unlike NRC’s policy advisory role, the aim of this review is an evidence-based determination of jet fuel carcinogenicity. Overall, this review provides an updated, more nuanced understanding of jet fuel’s carcinogenic potential that can inform future research priorities and regulatory considerations.

The determination of suggestive evidence of carcinogenic potential for jet fuels aligns with what is known about the carcinogenic potential of its components. For instance, benzene, one of jet fuels minor components, is a known human carcinogen^{6,7,50,152,153} and is causally linked to acute myelogenous leukemia via occupational inhalation exposure.^154–157 Similarly, ethylbenzene, a component of the corrosion inhibitor DCI-4A added to JP-4, JP-5, and JP-8, has been classified as possibly carcinogenic to humans by IARC based on evidence of carcinogenicity in experimental animals.^152,158,159

The carcinogenicity of kerosene, jet fuel’s primary chemical constituent, has not been definitively determined. While the American Conference of Governmental Industrial Hygienists has designated kerosene as a confirmed animal carcinogen with unknown relevance to humans,¹⁶⁰ earlier reviews from IARC¹⁵⁰ and ATSDR¹⁶¹ found limited evidence in animals, which was insufficient to determine carcinogenicity in humans. Animal studies reviewed by the IARC (1989) showed an increase in tumor incidence after dermal kerosene exposure, though the reviewers determined that the effect was unlikely to be due to genotoxicity.¹⁵⁰ ATSDR’s review also identified reports of increased inflammation, edema, hyperplasia, and necrosis in mouse skin following dermal application of kerosene.¹⁶¹ Subsequent animal toxicological research supports the hypothesis that tumor development from kerosene and jet fuel exposure may result from chronic irritation rather than genotoxicity. Nessel et al (1999) assessed both kerosene and jet fuel, observing similar effects for both substances: skin irritation and increased tumor frequency when applied undiluted.⁴⁹ Our assessment, integrating mechanistic evidence related to the KCCs, aligns with these findings, suggesting that tumor formation following jet fuel exposure may not be driven by genotoxicity but rather by chronic inflammation and immunosuppression.

More recent epidemiologic studies have signaled a potential link between exposure to kerosene combustion products and cancer risk in humans. Sheikh et al (2020), for instance, observed an association between inhalation of kerosene combustion products and an increased risk of esophageal cancer.¹⁶² However, exposure to liquid kerosene or its vapors may have different effects than inhalation of its combustion products, and the limited number of studies available has yielded mixed results. In addition to their findings on jet fuel, Siemiatycki et al (1987) reported elevated rates of stomach cancer incidence in workers exposed to kerosene; however, this association was driven by an increased risk of stomach cancer in forestry workers, whose kerosene exposure was classified as nonsubstantial.⁴⁰ Ritz (1999) also observed higher gastrointestinal cancer incidence (esophagus and stomach) and mortality rates (all gastrointestinal sites combined) among uranium-processing workers following long-term exposure to kerosene.¹⁶³ While these findings are inconclusive, they underscore the need for further research into the potential carcinogenic effects of jet fuels and their chemical constituents.

Data Gaps and Limitations

This systematic review of cancer outcomes associated with exposure to jet fuels incorporated recent publications across epidemiologic, animal toxicological, and mechanistic evidence streams. However, the literature remains insufficient to definitively conclude whether jet fuels are carcinogenic to humans. This review identified only 10 epidemiologic studies on cancer outcomes associated with occupational jet fuel exposure. None of the epidemiologic studies were considered high confidence, and only one was considered medium confidence. The remaining nine low confidence studies had substantial methodological limitations, including participant selection bias, imprecise exposure assessment, low sensitivity due to small numbers of jet fuel exposed participants, and residual confounding. Similarly, only 12 animal toxicological studies were identified, and study confidence levels were primarily low or uninformative, with only one high confidence study identified.

Occupational exposures are inherently complex, as workers are frequently exposed to multiple agents through multiple pathways rather than to a single substance in isolation. Several epidemiological studies identified specific probable co-exposures among their study participants including synthetic fuels, gasoline, and organic solvents, which were not the primary exposure of interest in this review. Some of these likely co-exposures are known or probable human carcinogens, such as chromium VI, benzene, and TCE, which could affect the apparent association between jet fuel exposure and incident.^18,33,35,36 Other reviewed studies that defined jet fuel exposure based on job titles alone included occupations in which exposure to liquid jet fuel was likely to occur alongside exposure to jet fuel combustion products (eg, military aviation ground crew).^34,36,37,45 This overlapping pattern of exposures complicates assessment of their independent contributions to cancer risk.

All epidemiologic studies were rated as deficient for exposure assessment in the study quality evaluations mainly because none used quantitative methods.¹³ Still, within this rating category, the studies differed in their methods and in their specificity for identifying jet fuel. Two related studies used semistructured interviews to obtain detailed occupational histories, which chemist-hygienists reviewed and translated into potential exposures using a standardized checklist.^40,41 This approach, developed by Siemiatycki et al (1987), represented the most rigorous method among the reviewed studies; but it remained limited by recall bias, particularly in Parent et al (2000), which incorporated population controls, and by reliance on qualitative judgments such as the chemist-hygienist’s confidence that exposure occurred.⁴² Reed et al(2020) employed a questionnaire to collect job task-specific information, capturing more detail than a simple job history, but was still subject to recall and reporting bias from self-reporting.⁴⁴ Four studies classified jet fuel exposure solely based on job titles, an efficient method but prone to misclassification given the heterogeneity of job tasks within occupation groups.^18,34–36 Finally, three studies assessed cancer risk by occupation without specifying hazards of concern. Although jet fuel is recognized as a substantial exposure for military aircrew, ground crew, aircraft handlers, and personnel involved in fuel-tank entry, individuals in these occupations are subject to a variety of exposures.^33,37,45 Without disentangling the relative contribution of fuel from other exposures, observed health outcomes cannot be definitively attributed to jet fuel.

Of the 10 epidemiologic studies reviewed, three estimated cancer incidence or mortality among jet fuel exposed populations using SIRs or SMRs relative to general populations.^33,35–37 Across these studies, cancer mortality rates observed in jet fuel exposed groups were consistently lower than expected based on general population reference rates. The authors of these studies attributed this pattern partially to the healthy worker or healthy soldier effect. Given cancer’s complex etiology and its extended prediagnostic phase, which may be unlikely to affect employment,^164,165 some argue that the healthy worker effect might be less pronounced in cancer research. Still, multiple recent studies have observed a persistent pattern of lower cancer incidence and mortality among employed people,^166–168 and among service members and veterans,^169–173 than in the general population. These findings underscore the potential impact of the healthy worker effect to mask true associations between occupational exposures and cancer risk.

Two epidemiologic studies presented cancer mortality findings without parallel incidence data from their study populations.^18,35 As rates of survival for many cancers have improved over time and many cancers do not necessarily result in death, mortality may inadequately capture the true cancer risk associated with occupational exposure. The use of an internal comparison group by Radican et al (2008) may have partially mitigated survivor bias by reducing confounding by factors related to healthcare access and socioeconomic status that strongly influence cancer survival. Relying exclusively on mortality data could lead to underestimation of exposure-related cancer risk, but considering the relevance of cancer site specificity, tumor aggressiveness, and survival outcomes in determining carcinogenic potential, incorporating mortality studies remains essential for a comprehensive assessment of the health effects of jet fuel exposure.

To overcome some of these limitations of occupational epidemiology, this review incorporated findings from animal toxicological and mechanistic studies. Animal models offer controlled dosing and exposure conditions, enable evaluation of different routes of exposure (eg, dermal tumor development following dermal exposure), and allow for assessment of dose-response relationships and recovery phases. However, the animal studies we assessed had limitations: they were often designed as long-term exposure studies focusing on broad outcomes such as organ histopathology and mortality and they frequently did not clarify the underlying mechanisms of action but sometimes speculated based on primary literature and historical data. Mechanistic studies helped fill these gaps by providing evidence for biological plausibility and insights that explain concordance between human and animal findings. When interpreted alongside findings from human studies, the integration of animal toxicological and mechanistic evidence provides a comprehensive assessment of the potential risks of jet fuel exposure.

Heterogeneity in Study Designs

Conclusions made based on the current epidemiologic evidence base were limited by a lack of consistency in terms of the cancer outcomes evaluated and by several other factors related to study design. Including both incidence and mortality endpoints, 16 specific cancers were assessed in the 10 epidemiologic studies. Six cancers (brain and nervous system, leukemia, melanoma, oropharyngeal, stomach, and thyroid) were each assessed in a single study. Kidney cancer was the only type of cancer showing a significant association in more than one epidemiologic study, but both of these studies drew from the same study population.^40,41 Non-Hodgkin lymphoma was assessed in six studies, none of which observed a significant association with jet fuel exposure. Finally, only one study reported on leukemia incidence related to occupational jet fuel exposure (no significant adverse association was observed), despite jet fuel containing benzene, a well-established carcinogen linked particularly to leukemia.³⁴ This lack of consistent findings could be the result of differences in the underlying risk of cancer across study populations. It could also be related to heterogeneity in study designs, small effect sizes, or the varying latency periods of specific cancers. Additional studies are needed to reproduce findings in the existing evidence.

Animal toxicological studies showed more consistency in cancer endpoints than the epidemiologic studies. The majority assessed outcomes in the skin (9 studies), kidneys (7 studies), lung (7 studies), and liver (7 studies); however, investigators used various jet fuels, doses, and routes of exposure. The 12 studies reviewed examined nine different fuels, including four that were each examined in a single study and by a single route of exposure (JP-10/inhalation, JP-7/inhalation, JP-TS/inhalation, and JP-5/dermal). JP-8 exposure was assessed in two studies via inhalation. The most consistent evidence was provided in three studies on Jet A, all of which observed significantly higher incidence of skin cancers following dermal exposures.^47–49 Results from three JP-4 inhalation studies were mixed, with two showing no changes in any evaluated organ and one reporting some significant species- and sex-specific effects.^26,27,32

Homogeneity of Study Populations

The small set of epidemiologic studies identified in this review represented a small number of distinct study populations. Spirtas et al (1991) and Radican et al (2008) evaluated cancer-related mortality in a cohort of civilian workers at Hill AFB, Utah.^18,35 Siemiatycki et al (1987) and Parent et al (2000) both evaluated jet fuel exposure history in cancer patients in Montreal, Canada.^40,41 These studies were different enough in their comparison populations, outcomes, and analytical methods to be considered independently in the synthesis of evidence. However, because of the similarity of the study populations and exposure scenarios, they added less weight toward the consistency criteria for causation. While it was efficient to revisit existing cohorts, and there may be more to learn over a longer follow-up period and as additional health events accumulate, more studies are needed to assess the association between jet fuel exposure and cancer outcomes in different populations and settings.

The homogeneity of the study populations may also limit the generalizability of findings to all jet fuel-exposed workers. Five of 10 epidemiologic studies were conducted in military populations, and two were conducted in civilian workers at a military installation. The exposure scenarios for these populations are likely to be comparable to other military populations but may not be generalizable to other civilians. The study populations were also demographically homogeneous. The cohort of civilian workers at Hill AFB assessed in two studies was 97% White.^18,35 Only two other studies described the racial distribution of their study populations, including D’Mello and Yamane (2007), whose cohort of active-duty Air Force service members included a higher proportion of White participants than the USAF population in 1995 (the midpoint of their study period).³⁴ Furthermore, three of the studies that assessed nonreproductive cancers limited their study population to males only. Only D’Este et al (2008) documented the reason for this selection, stating that the number of women exposed to DSRS was small.³³ Six studies include both males and females, and four of these presented sex-stratified analyses. Studies on jet fuel exposure and cancer risk primarily conducted on White and/or male workers may not accurately reflect outcomes for non-White and/or female workers due to the potential for occupational differences affecting exposure characteristics, unique cancer susceptibilities, and disparities in diagnosis and survival.^174,175 Future epidemiologic studies should consider incorporating more diverse populations.

Diversity in animal models was also limited. Mice (8 studies) and rats (8 studies) were the most common animal models used. Most studies in mice and rats were further limited to a single strain (5 studies each in C57BL/6 mice and F-344 rats). One low confidence study also assessed cancer outcomes in hamsters and dogs,³¹ and one uninformative study assessed cancer outcomes in dogs and monkeys.^31,32 The three animal studies that found elevated incidence of kidney cancer observed the effect exclusively in male F-344 rats.^27,28,31 The authors attributed the results to α2μ-globulin nephropathy syndrome, a condition unique to male rats, therefore it is not clear that these findings translate to humans. A wider range of animal models would provide a more comprehensive assessment of cancer outcomes, as the ability of these models to predict human toxicity varies across different organ systems and toxicants.¹⁷⁶ Mechanistic studies, which are not constrained by species-specific conditions, can also address this limitation and reduce uncertainty. The current mechanistic evidence suggests that jet fuel exposure may trigger inflammatory and immunosuppressive responses at the cellular level, which could create conditions conducive to tumor initiation and progression. Although all studies assessing epigenetic alterations reported jet fuel-induced modifications, the limited number of studies prevents definitive conclusions. In addition, the lack of research on electrophilicity, DNA repair, and cellular immortalization, identified in this report highlights the need for future mechanistic studies to determine whether jet fuel can induce these modifications.

Inadequate Exposure Characterization

Characterizing exposure to jet fuels in humans is complicated by the variety in potential routes of exposure, exposure levels, and the likelihood that individuals experience multiple concurrent exposures. Given these complexities, most of the epidemiologic studies identified by this review assessed jet fuels as a group, rather than focusing on specific types. This approach acknowledges the practical difficulty of isolating the effects of individual jet fuel types from other workplace exposures, which may include a mix of fuels, solvents, and emissions. However, it limits the ability to attribute any observed effects to specific fuels or constituents. Additional animal toxicological studies and/or improved exposure monitoring could enhance the understanding of the contribution of specific hazards, as well as the potential mixtures, experienced in these workplace environments on the observed health outcomes. Currently, there is a shortage of replicated findings in the published evidence, especially concerning the most widely used jet fuels, JP-5 and JP-8. More reproducible studies are needed to better understand the health implications of these fuels.

Limited Coherence Across Evidence Streams

The coherence of evidence across epidemiologic and animal toxicological studies is also limited. Only kidney cancer was observed in both humans and animals following jet fuel exposure. Two epidemiologic studies observed an increase in kidney cancer in men occupationally exposed to jet fuel,^40,41 and one observed a high rate of in kidney cancer in US military ground crew, relative to the US general population.³⁷ Three animal toxicological studies observed an increase in kidney neoplasms in male rats following inhalational exposure to JP-4, JP-7, JP-10, or JP-TS, although the probable mechanism for the observed increased cancer incidence (α2μ-globulin nephropathy syndrome) is unique to male rats and is not considered relevant to humans.^27,28,31 Four other animal studies assessed dermal cancers following treatment of the skin with jet fuels, with three studies observing a significantly increased incidence.^47–49 While no epidemiologic studies reported significant associations between occupational jet fuel exposure and skin cancers, one case report described an epithelioid sarcoma on the hand of a USAF Senior Airman with occupational exposure to jet fuels, including hydrazine.⁴⁶ The mechanistic evidence also supports a mechanism for jet fuel to cause skin cancer. A substantial percentage of studies identified an exacerbated inflammatory response in the skin of dermally exposed animals, which is relevant to KC 6 (Induces Chronic Inflammation).

Although coherence across epidemiologic, animal, and mechanistic studies is currently limited, several approaches could help strengthen these connections. More targeted epidemiologic studies with refined exposure assessments and longer follow-up, along with animal studies that better mimic occupational exposure, would improve comparability. Emphasizing human-relevant mechanistic pathways (eg, inflammation, oxidative stress, DNA damage) and applying structured frameworks such as the KCCs can further integrate findings and highlight consistencies despite current gaps.

In summary, this review assessed the findings of 10 epidemiologic studies, one case report, 12 animal toxicological studies, and supporting mechanistic evidence. The majority of both epidemiologic and animal toxicological studies were classified as low confidence or uninformative, and there was limited consistency in exposure or outcome across studies. Still, the overall weight of evidence was determined to reach the level of suggestive evidence of carcinogenic potential according to the Guidelines for Carcinogen Risk Assessment.¹¹ Additional studies are needed to confirm existing studies’ findings and establish a mode of action if one exists.