Review Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures [...], 2015, White et al

[forestglip]

Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment

Roberta F White, Lea Steele, James P O’Callaghan, Kimberly Sullivan, James H Binns, Beatrice A Golomb, Floyd E Bloom, James A Bunker, Fiona Crawford, Joel C Graves, Anthony Hardie, Nancy Klimas, Marguerite Knox, William J Meggs, Jack Melling, Martin A Philbert, Rachel Grashow

Published: 2015

Abstract
Veterans of Operation Desert Storm/Desert Shield – the 1991 Gulf War (GW) – are a unique population who returned from theater with multiple health complaints and disorders. Studies in the U.S. and elsewhere have consistently concluded that approximately 25–32% of this population suffers from a disorder characterized by symptoms that vary somewhat among individuals and include fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal and dermatologic complaints. Gulf War illness (GWI) is the term used to describe this disorder. In addition, brain cancer occurs at increased rates in subgroups of GW veterans, as do neuropsychological and brain imaging abnormalities.

Chemical exposures have become the focus of etiologic GWI research because nervous system symptoms are prominent and many neurotoxicants were present in theater, including organophosphates (OPs), carbamates, and other pesticides; sarin/cyclosarin nerve agents, and pyridostigmine bromide (PB) medications used as prophylaxis against chemical warfare attacks. Psychiatric etiologies have been ruled out.

This paper reviews the recent literature on the health of 1991 GW veterans, focusing particularly on the central nervous system and on effects of toxicant exposures. In addition, it emphasizes research published since 2008, following on an exhaustive review that was published in that year that summarizes the prior literature (RACGWI, 2008).

We conclude that exposure to pesticides and/or to PB are causally associated with GWI and the neurological dysfunction in GW veterans. Exposure to sarin and cyclosarin and to oil well fire emissions are also associated with neurologically based health effects, though their contribution to development of the disorder known as GWI is less clear. Gene-environment interactions are likely to have contributed to development of GWI in deployed veterans. The health consequences of chemical exposures in the GW and other conflicts have been called “toxic wounds” by veterans. This type of injury requires further study and concentrated treatment research efforts that may also benefit other occupational groups with similar exposure-related illnesses.

Web | PDF | Cortex | Open Access

 

[forestglip]

Note this is not a new study. This is a very wide-ranging review of gulf war illness research published up to 2015.

I'm particularly interested in how sure they appear to be that pyridostigmine bromide (PB) (AKA Mestinon) and pesticides are causally linked to GWI.

GW personnel were often exposed to high levels of a variety of pesticides and insect repellants in theater.

The 1991 GW is the only conflict in which PB was widely used by military personnel as a prophylactic measure intended to protect against effects of possible nerve gas attacks

Across all studies and populations and since the earliest findings appeared linking self-reported exposures to diagnosis of GWI, two types of theater-related exposures have been consistently identified as risk factors for the disorder: exposures to pesticides and PB use.

In research controlling for concurrent exposures, pesticide exposures were significantly associated with GWI in six of seven GW populations evaluated, and PB exposure was significantly associated in all seven of the populations studied.

In addition, research that assessed the relationship between degree of exposure to pesticides and PB has consistently identified significant positive dose–effect relationships between degree of exposure and likelihood of GWI diagnosis (greater exposure is associated with higher likelihood of GWI diagnosis).

Table 4 summarizes all the PB and pesticide studies they looked at.

PB and at least some (maybe all, I haven't looked) of the pesticides that are associated with GWI are acetylcholinesterase (AChE) inhibitors. They also describe another potential mechanism of pesticides apart from affecting AChE:

OPs [organophosphate pesticides] have been shown to disrupt multiple functions beyond those linked strictly to AChE. While AChE inhibition from exposures that occurred in the GW (e.g., sarin and CPF) have been implicated in the etiology of GWI (Golomb, 2008), other studies have identified additional secondary pathways of OP effects apparently unrelated to inhibition of AChE (see review; Terry, 2012). A notable non-cholinergic target of OPs is the process of axonal transport, a key nervous system function for transporting molecules (e.g., RNA and proteins) and subcellular organelles (e.g., mitochondria and synaptic vesicles) through the cytoplasm of axons (Terry, 2012).

I'm curious what dose of PB the military personnel were taking and if it's significantly higher than the dose often prescribed for orthostatic intolerance.

They say connections to other exposures (nerve agents, oil well fire smoke, vaccines) are less clear, or show more consistent evidence of links to conditions like brain cancer and respiratory disorders, as opposed to directly to GWI.

 

[forestglip]

I'm curious what dose of PB the military personnel were taking and if it's significantly higher than the dose often prescribed for orthostatic intolerance.

Information from Veterans Affairs:

Supplied in the Gulf War as 21-tablet blister pack, with prescribed dosage as one 30-mg tablet every 8 hours. Veterans’ actual exposure is not known, because pills were self-administered and there are few examples in individual or unit health records from the Department of Defense.

Bateman Horne Center says this for dosages for orthostatic intolerance:

The doses usually range from 30-60 mg every 4-6 hours depending on tolerance and response. There is a 180 mg extended-release version.

Interestingly, potentially lower dosage for military than for OI patients.

 

[forestglip]

Hmm, the veterans affairs website says:

VA has concluded that the evidence does not support an association [with pyridostigmine bromide]. Read the Federal Register notice for the rationale behind VA’s decision.

The file it links to is a 2011 document, but the above study (which appears to be commissioned by the VA) is from 2015.

Edit: See appendix A for the literature review from the VA in 2009 that found the evidence was not sufficiently strong to connect PB or pesticides to GWI:

Committee on Gulf War and Health: Health Effects of Serving in the Gulf War, Update 2009

Edit 2: The Volume 10 update from 2016 still says the evidence is too weak.