From Combustion Emissions to Neurotoxicity: Brain Health Risks of Military Burn Pits Exposure

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a timely narrative review that makes a strong case for military burn pit exposure as a complex combustion-related health risk with potential consequences from the respiratory system through to neurological impact. The manuscript is well structured, and integrates exposure science together with neuroinflammation, and neuropsychiatric outcomes, and is particularly valuable to framing of the lung-brain axis as a biological pathway linking inhaled toxins to cognitive and other symptoms in Veterans. The review is suitable for publication after minor revision, mainly to improve some minor methodological information, tighten some language, and correct some minor inconsistencies.

Minor points:

1. The manuscript states that it is a narrative review informed by systematic search principles and lists search terms, databases and inclusion criteria, but the process remains a bit under-described for a review that reports ‘106 out of 364’ records. Can the authors add more detail on screening, duplicate removal, eligibility assessment, and how final studies were selected. Lines: 95-121; Table 1, lines 108-109.
2. Several statements imply a causation from burn pit exposure to neuropsychiatric outcomes where the evidence is currently somewhat mixed, or extrapolated from related combustion exposures. e.g, the authors state that burn pit emissions contribute to PTSD, depression, TE and cognitive impairment, while later acknowledging that the causality is difficult to establish. Maybe the authors can consider consistently using phrasing such as ‘may contribute to’, ‘is associated with’, or something like this Lines: 25-35, 70-87, 607-613, 631-646.
3. The Figure 1 caption states that CRH is secreted ‘in the pituitary’, but which should be secreted ‘in the hypothalamus’. Lines: 420-425.
4. The manuscript effectively links TE, cognitive impairment, depression and PTSD through shared mechanisms, but at times TE is presented as a broad umbrella for symptoms that may also arise independently from trauma, sleep disorders, pain, TBI, or psychiatric comorbidity. Maybe the authors could more clearly distinguish TE as a diagnostic entity from overlapping symptom clusters in exposed Veterans. Lines: 462-480, 513-519, 624-630.
5. The conclusion is good, but it could more explicitly state that the strongest evidence supports biological plausibility and concern, while longitudinal human studies with exposure characterization and brain-specific biomarkers still remain needed to strengthen this. This would align better with the conclusion of the manuscripts own limitations and future directions. Lines: 664-682.

Author Response

Please attached document for our responses to reviewers.  

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The article is a good summary and systematic review of the existing literature, pending minor revisions detailed below, the article is a positive contribution to military health.

 

Detailed comments:

Table 1, line 108;  Why were systematic reviews included?  Doing a review of a review seems redundant and also does not allow the authors of this paper to critically assess the original work and put it in perspective with the other literature reviewed.   If this was simply done to be sure that they were able to gather all possible original research articles, then this would make sense.  However, if this were done to simply summarize something that is already a summary, that would be duplicative.

 

Line 237, the authors state,   “Following inhalation, VOCs are rapidly absorbed across the alveolar-capillary barrier due to their lipophilicity and distributed systemically [31]” however the authors need to be more specific, that article they cite is about benzene not about VOCs in general, while it is true that generally poor combustion can generate more lipophilic compounds, we also know that there are polar compounds that can also be generated depending on the combustion conditions and make-up of the fuel (e.g. burning fuels with ethanol additives likely generate some polar compounds too).  Hence, the authors should just say “benzene” or qualify their statement more clearly.

 

Line 249 – 251, the authors state, “Importantly, VOCs can distribute be-249 yond the lung and have been associated with central nervous system effects, including 250 cognitive impairment and mood-related symptoms observed in exposed populations 251 [35,36]. “ but the articles cited are for jet fuel JP-8 and contaminates at Camp LeJune, perhaps the authors should make a more conditional statement by saying something like “many VOCs…..” rather than an absolute statement as written, which reads all VOCs.

 

Line 260, while this is true “many PAHs are less volatile ….”   It is still worthwhile to point out that they still have some volatility and can result in airborne exposures, whether on the surface of particles or as a vapor, the example given with naphthalene is an example, while semi-volatile it has a strong odor and can result in some vapor exposures too.

 

Line 266-269, the authors state “PAHs can remain in the body for weeks, allowing for accumulation and passage across the blood-brain barrier as critical concentrations of PAHs outside of the BBB cause the PAH particles to shift to the lower concentration area in the CNS 268 [41].”    Do the authors mean diffusion across the BBB?  If so, they should state that.    Also citation #41 appears to be a literature review, it would be much better for them to include the original research article that shows this phenomenon rather than just a review that cited it.    

 

Line 311 reference 44:  The authors attribute the observation of the cited paper to inhalation exposure, however, the article is from a psychiatry journal and the title indicates it is about post-traumatic stress disorder, as such the authors need to more clearly articulate how this reference shows any evidence for the impact of air pollutants.

 

                -more broadly, the papers cites many references that claim an observation of an impact of combustion pollutants on health including some epidemiologic studies but also a lot of lab-based studies, it would be important to put all of these studies in context as we often observe things in the lab or toxicology studies that don’t necessarily happen in “real-life” because the doses, exposures, etc. are often different in lab studies compared to “real life”.  Some discussion to put this in context would be helpful, how does this all work out when you have many other issues (such as post-traumatic stress disorder) that also are occurring concurrently with the air pollution exposure in “real life scenarios”?   How does Socioeconomic status and other confounders impact the epi studies and what does this mean for the interpretation of the toxicology studies?   How does this apply to “real life” and what are the limitations in the application of these studies to actual real military populations?   Relative to the stress of fighting and being in the military, is this really significant or important?

 

Line 391:  reference 51 does not appear to have any relationship to the statement made, reference 51 is about chemical characterization of emissions form a simulated burn pit not about impact on neurological systems, the authors should not cite an paper that cites another paper, rather they should get the original reference and review that original reference and cite that paper.

 

Line 420, figure 1 – so this figure is for the normal negative feedback loop, and the text then indicates that combustion derived pollutants interfere with this feedback loop, which I presume would mean that the red lines in the figure would be blocked?   A visual of the interference from the pollutants in this figure would be helpful.

 

Line 480, the authors speculate about TE and burn pits, can they comment on whether this could be coincidental or the result of the stress of fighting/deployment rather than from their burn pits?  Some limitation of their interpretation may be warranted here since the common symptomology reported can be associated with many causes and many different diseases.

 

 

Author Response

Please attached document for our response to reviewer comments.  

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Overall comment:

This is a well-written and timely review that evaluates the relationship between combustion emissions from military burn pits and adverse neurological outcomes. The manuscript is generally in strong shape; however, several revisions could further strengthen its rigor and broaden its impact.

First, the discussion of contaminants is largely focused on compounds generated from the combustion of organic materials (e.g., PAHs, VOCs, particulate matter). It would be valuable to expand this scope, or explicitly acknowledge as a limitation, to include compounds associated with the combustion of synthetic materials. For example, organophosphate ester flame retardants, polybrominated diphenyl ethers (PBDEs), dioxins/furans, and per- and polyfluoroalkyl substances (PFAS) are increasingly recognized as important exposure concerns during fire responses. Studies in firefighters have demonstrated elevated exposure to many of these compounds, and I would assume that military personnel exposed to burn pits may encounter similar risks. If direct evidence of these exposures in military populations is limited, this gap should be highlighted as an important direction for future research.

Second, the manuscript would benefit from incorporating emerging literature on epigenetic changes associated with combustion-related exposures. In particular, recent studies in firefighters have identified microRNA and other epigenetic alterations linked to pathways involved in adverse neurological outcomes. Integrating this work could provide a more mechanistic perspective on how exposures translate to neurotoxicity.

Finally, comparisons of measured contaminant levels to exposure standards should be revisited. Given the occupational context, it would be more appropriate to reference benchmarks such as OSHA Permissible Exposure Limits (PELs), NIOSH Recommended Exposure Limits (RELs), and Military Exposure Guidelines (MEGs), rather than U.S. EPA ambient standards. Ensuring that these comparisons are accurate and context-appropriate will improve the interpretability of the findings.

I have provided some specific comments below:

 

 

Comment: Line 56, has there been any research looking at compounds found in synthetic materials, like organophosphate ester flame retardants, polybrominated diphenyl ethers, dioxins, and per- and polyfluoroalkyl substances (PFAS)?

 

Comment:  Line 137: Reference #7 appears to be a thesis submitted as part of a masters program. Please consider clarifying.

 

Comment: line 137: Given we are talking about occupational exposures, a better comparison would be to OSHA’s Permissible Exposure Limit (PEL), NIOSH’s recommended exposure limit (REL), or the Military Exposure Guidelines (MEG). Benzene concentrations in reference 12 were well below those thresholds.

 

Comment:  line 137: I’m not sure you should be citing reference 7 here, and reference 12 does not find elevated PAHs

 

Comment:  Line 233: could you provide the MEG here? additionally, consider comparing to NIOSH PEL or OSHA RELs if it’s useful

 

Comment: line 256: PAHS has previously been defined in the intro

 

Comment: Line 256: probably worth highlighting some studies that find firefighters are exposed to PAHs at elevated concentrations.

 

Comment:  A study found elevated concentrations of naphthalene and dioxin/furans in human serum from military personnel exposed to burn pits. I think this would be a good addition to your evaluation: Xia X, Carroll-Haddad A, Brown N, Utell MJ, Mallon CT, Hopke PK. Polycyclic Aromatic Hydrocarbons and Polychlorinated Dibenzo-p-Dioxins/Dibenzofurans in Microliter Samples of Human Serum as Exposure Indicators. J Occup Environ Med. 2016 Aug;58(8 Suppl 1):S72-9. doi: 10.1097/JOM.0000000000000743. PMID: 27501107; PMCID: PMC4977992.

 

Comment: Some recent papers have found that exposed firefighters have microRNA changes in pathways that are related to adverse neurological outcomes. I think it would be worth adding some discussion about this work:

 

Furlong MA, Liu T, Jung A, Beitel S, Hughes J, Krause R, Graber JM, Calkins MM, Calafat AM, Botelho JC, Huentelman M, Gulotta J, Goodrich JM, Burgess JL. Per- and polyfluoroalkyl substances (PFAS) and microRNA: An epigenome-wide association study in firefighters. Environ Res. 2025 Aug 15;279(Pt 2):121766. doi: 10.1016/j.envres.2025.121766. Epub 2025 May 9. PMID: 40350013; PMCID: PMC12203895.

Goodrich JM, Xin Y, Beitel SC, Gulotta J, Wang L, Thotakura B, Graber JM, Urwin D, Mayer AC, Jahnke S, Edwards DL, Grant C, Ranganathan S, Burgess JL. Differences in MicroRNA Expression in Firefighters Responding to a Train Derailment and Fire in East Palestine, Ohio. Epigenomes. 2026 Feb 3;10(1):8. doi: 10.3390/epigenomes10010008. PMID: 41718406; PMCID: PMC12921792.

Author Response

Please attached document for our response to reviewer comments.  

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

I think this review can be accepted after some revisions.

1. At the end of introduction section, a scheme should be added to summarize the outline of this review.
2. The outline of this review is just like a research paper rather than a review paper, at least the title of each section should be revised.
3. If necessary, some references should be cited in the captions of the figures.
4. Please add some sentences about the summarization of each research point.
5. Please enhance the connectivity of each section.

Author Response

Please attached document for our response to reviewer comments.  

Author Response File: Author Response.pdf