Toxicant exposures and Gulf War Syndrome

Of the various directions away from autism research that I tend to take on this blog, discussions based on the collected [peer-reviewed] research literature on Gulf War Syndrome will always retain a special interest (see here). Not least because here we have a group of some of our bravest men and women who went out to liberate Kuwait in the early 1990s and who came back home in an often quite appalling state and thereafter basically left to rot.

I know that might all sound a little dramatic but after having met one or two veterans down the years and seen first hand how their health and well-being has been affected following their deployment to the Persian Gulf all those years ago I'm just telling it like it is. As much due to political reasons as scientific ones, the plight of these veterans - who really only want to know what happened to them and some acknowledgement that something 'did' happen to them outside of it being wholly 'psychosomatic' - has been the source of much controversy and debate down the years. Now at last it appears that a consensus based on the available science might have been reached [1]: "the research to date supports the conclusion that veterans are suffering from a "persistent pathology due to chemical intoxication.""

The paper by Roberta White and colleagues (someone not unfamiliar to Gulf War research) carries that conclusion and is open-access for all to read. Following a lengthy review of the various exposures that faced veterans and the likelihood of them (adversely) affecting their health, the authors detailed a few 'bottom lines'.

To quote:

"Between one-fourth and one-third of deployed GW [Gulf War] veterans are affected by a disorder characterized by chronic symptoms involving multiple body systems; this condition is best identified by the term GWI [Gulf War Illness]."

Further:

"This disorder was caused by toxicant exposures, individually or in combination, that occurred in the GW theater. At present, research most clearly and consistently links pesticide and PB [pyridostigmine bromide] exposures to GWI, while exposures to low-level nerve gas agents, contaminants from oil well fires, multiple vaccinations, and combinations of these exposures cannot be ruled out."

And also:

"Further research into the mechanisms and etiology of the health problems of GW veterans is critical to developing biomarkers of exposure and illness and preventing similar problems for military personnel in future deployments; this information is also critical for developing new treatments for GWI and related neurological dysfunction."

I'm sure you'll agree that these are pretty important conclusions. That also the authors talk about the potential overlap between GWI and other states specifically related to exposure to organophosphate (pesticides) such as during pesticide application (see here) or during sheep dipping (those with so-called dippers flu) is another important element. I say this not to somehow come down too hard on organophosphate (OP) pesticides, which serve an important purpose in modern agriculture and the like, but merely to reiterate that (a) caution is needed in their handling and use, and (b) they are chemically-speaking, not a million miles away from some of the most toxic nerve agents the world has ever seen. Indeed, with all the talk about Zika virus these past weeks (see here) I'm minded to suggest that one might need some additional controls in place to ensure the safe use of OPs when controlling the insect carrier (see here).

Bundled alongside the various chemical exposures - and other events [2] such as exposure to depleted uranium - that might be linked to symptoms is the added suggestion that "multiple vaccinations" may have also played a role in the presentation of the condition for some [3]. When I say vaccinations, the data suggests that these weren't just routine vaccinations against your typical childhood diseases, but rather included those aimed at a slightly more unusual disease set such as anthrax and plague (see here). The jury is still out on the extent to which these agents (singularly or combined) might have contributed to symptoms but I'm minded also to bring in the concept of ASIA (‘autoimmune (auto-inflammatory) syndrome induced by adjuvants’) that has been mentioned with GWI in mind (see here) as potentially being relevant.

Of course, more research is indicated on many aspects identified by White et al including the idea of some overlap between GWI and the presentation of chronic fatigue syndrome (CFS) [4] being careful with how wide we cast the CFS diagnostic net [5]. Alongside, perhaps one might think that an apology or two to some of our brave veterans wouldn't also go amiss from Government and others following various comments made down the years about the nature of their illness.

And for those who still might scoff at the idea of the 'toxic' effects of war, the chemical legacy of another campaign still continues to haunt some to this day...

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[1] White RF. et al. Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment. Cortex. 2016; 74: 449-475.

[2] McDiarmid MA. et al. Health effects of depleted uranium on exposed Gulf War veterans. Environ Res. 2000 Feb;82(2):168-80.

[3] Unwin C. et al. Health of UK servicemen who served in Persian Gulf War. Lancet. 1999 Jan 16;353(9148):169-78.

[4] Ismail K. et al. Chronic fatigue syndrome and related disorders in UK veterans of the Gulf War 1990-1991: results from a two-phase cohort study. Psychol Med. 2008 Jul;38(7):953-61.

[5] Jason LA. et al. Unintended Consequences of not Specifying Exclusionary Illnesses for Systemic Exertion Intolerance Disease. Diagnostics (Basel). 2015 Jun 23;5(2):272-86.

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White RF, Steele L, O'Callaghan JP, Sullivan K, Binns JH, Golomb BA, Bloom FE, Bunker JA, Crawford F, Graves JC, Hardie A, Klimas N, Knox M, Meggs WJ, Melling J, Philbert MA, & Grashow R (2016). Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment. Cortex; a journal devoted to the study of the nervous system and behavior, 74, 449-75 PMID: 26493934

Gulf War agents and delayed onset of symptoms in mice

I was recently intrigued by the findings reported by Zuchra Zakirova and colleagues [1] (open-access) on what happened to mice following 'acute' exposure to pyridostigmine bromide (PB) and the pesticide permethrin (PER) in the context of these compounds being "key contributors to the etiology of GWI [Gulf War Illness] post deployment to the Persian GW [Gulf War]."

I've covered the topic of Gulf War Syndrome (GWS) before on this blog (see here) and how, following one of the most toxic wars in history, quite a few service personnel (and local civilians) developed an array of symptoms which still confuse science and medicine today. There is no doubt that the conflict in 1990-1991 presented the military with a pretty hostile environment; not least because of the setting in the Persian Gulf. This was further compounded by burning oil fields, a variety of potential chemical exposures (including some rather nasty nerve agents) and issues like depleted urinanium tipped munitions to contend with. All-in-all, not a great place to be.

"We hypothesized that co-administration of PB and PER in our mouse model of GW agent exposure would recapitulate the late-onset symptom multiplicity and heterogeneity of symptoms observed in GW veterans, such as memory deficits and neurological deficits." That was the rationale behind the study bearing in mind that this was a study of mice for obvious ethical reasons.

Said mice - "Forty-eight male C57BL6/J mice" - were given either the PB/PER mix (via intraperitoneal injection) or 100% DMSO (as a control). As you may appreciate, direct injection of PB/PER is probably not the same kind of exposure that veterans would have come across in active theatre. PB as NAPS (nerve agent pre-treatment tablet set) was given in an oral dosage form. PER would probably have been delivered as a cream (or aerosol). One perhaps needs to keep this potentially important difference in mind when interpreting the Zakirova findings.

Dividing the mice groups up into a short-term cohort and a long-term cohort (18 days post exposure vs. 5 months post exposure respectively), various 'neurobehavioural' testing was undertaken on the cohorts. The mice participants were eventually euthanized so that any "neuropathological changes associated with GW agent exposure" could also be investigated.

There were some interesting results (and non-results) to be had from the amassed data. Short-term exposure to the PB/PER mix resulted in, well, not very much difference when compared to control animals: "No cognitive deficits were observed at the short-term time point, and only minor neuropathological changes were detected."

But longer-term, there were some potentially important differences noted between exposed and non-exposed animals. So for example: "Impairment for long-term memory formation was observed at day 106 days-post acute exposure to PB + PER." This was based on the results of a test of spatial memory. Further: "PB + PER exposure altered astrocytic activation in the hili of hippocampi and cerebral cortices of mice." Not being particularly au fait with all-things neuropathological, I can't readily put too much descriptive flesh on these experimental bones. I gather that "astroglial activation" might be something important when it comes to the destruction of neurons following injury or infection (but don't quote me on that). Potentially importantly too were the authors' findings that: "ACh [acetylcholine] levels were increased in the CNS [central nervous system] of exposed mice" and further "that exposure to GW agents may be attributed to the impaired cholinergic function observed in GWI and may in part contribute to deficits observed in long-term memory formation." I say this noting that permethrin is classified as a pyrethroid not an organophosphate (OP) which has a more classical relationship with acetylcholinesterase but PB has perhaps a more direct effect on acetylcholine.

Reiterating that the Zakirova study reports results based on mice and 'acute' exposure of said mice to potentially important agents, these are interesting results mirroring other studies from the authors [2]. I note that there may be more to see from this research group in future with the anticipation that "subsequent studies will provide us with a more lifetime picture regarding the long-lasting consequences of GW agent exposure." If this is indeed something that can be garnered from such a mouse model and given the significant suffering endured by many veterans, a little more scientific knowledge to illuminate the way would be very welcome.

Music: Tumbling Dice - The Rolling Stones.

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[1] Zakirova Z. et al. Gulf War Agent Exposure Causes Impairment of Long-Term Memory Formation and Neuropathological Changes in a Mouse Model of Gulf War Illness. PLoS One. 2015 Mar 18;10(3):e0119579.

[2] Ojo JO. et al. Exposure to an organophosphate pesticide, individually or in combination with other Gulf War agents, impairs synaptic integrity and neuronal differentiation, and is accompanied by subtle microvascular injury in a mouse model of Gulf War agent exposure. Neuropathology. 2014 Apr;34(2):109-27.

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Zakirova, Z., Tweed, M., Crynen, G., Reed, J., Abdullah, L., Nissanka, N., Mullan, M., Mullan, M., Mathura, V., Crawford, F., & Ait-Ghezala, G. (2015). Gulf War Agent Exposure Causes Impairment of Long-Term Memory Formation and Neuropathological Changes in a Mouse Model of Gulf War Illness PLOS ONE, 10 (3) DOI: 10.1371/journal.pone.0119579

The legacy of Desert Storm

This post represents a little bit of a departure from the my normal autism research-related musings. The topic however is something that has cropped up during the course of my career on several occasions. Read on and see more.

Having recently commemorated the shocking events of 10 years ago on that fateful Tuesday morning September 11th 2001, the repercussions of those atrocities continue to reverberate across the globe. Whilst Afghanistan remains an active theatre of operations, the memory is still fresh from Operation Iraqi Freedom and the whys and wherefores of that conflict that left so many families devoid of loved ones. Casting your mind back further to the early 1990s, and in particular the conflict known as Operation Desert Storm, some interesting questions still remain outstanding on the health implications to military and civilian populations alike as a result of the 'Video Game War'. A recent paper by Lea Steele and colleagues* published in the journal Environmental Health Perspectives provides further evidence (adding to a growing body of research) suggesting that deployed military personnel experienced various illnesses potentially as a result of several exposures on and off the battlefield.

It is perhaps important to make a few points before proceeding. As well as being the first modern action to be broadcast live to the masses, remembering all those picture of Tomahawk cruise missiles being deployed from the coaliton battlegroup, the 1990 Persian Gulf War has been described as one of the most toxic wars in history. Saddam Hussein and his followers were known to use chemical weapons on their own population as exemplified by the Halabja attack; an attack which is thought to have used various chemical agents including mustard gas and the nerve agents sarin and VX. Although the picture is still fuzzy about whether such agents were deployed against coalition troops, the environment was always going to be a hostile one for lots of other reasons such as burning oil fields and various depleted uranium tipped munitions employed on top of the various other hurdles posed by a pretty inhospitable natural environment. Although the subject of some debate in a dwindling number of quarters, it does appear that many deployed personnel returned from the conflict in a pretty poor state of health; indeed even 10 years after, their health was still the cause of some concern. Termed, 'Gulf War Illness' or 'Gulf War Syndrome', the US Department of Veteran Affairs website carries quite a lot of information about what the syndrome includes. I am going to stop there on the background data because the research base to the condition is huge and could take up a whole blog in itself.

Back to the Steele paper. Their findings based on 144 veterans who met author specified criteria for Gulf War Illness suggested that several different factors and scenarios might have been instrumental to their symptoms depending on whether personnel were in active theatre or not. For forward deployed troops, reported proximity to SCUD missile explosions and the use of pyridostigmine bromide (PB) pills, also called NAPS (anti-nerve agents), were associated with illness. For support personnel not seeing front line action, the use of pesticides on clothing or skin were associated with illness.

Bearing in mind various limitations of this paper, the results are complex yet interesting. I have previously touched upon pesticide exposure in relation to autism and what the various classes of pesticides might be capable of so won't give much more space to this factor aside from what is already known about the health effects of DEET and lindane. PB pills have long been the source of speculation in terms of their potential health effects. Professor Mohamed Abu Donia has published extensively on the 'interacting' effects of pesticides and PB medication. As for the SCUD explosions, I don't know. It does perhaps make you wonder what the payload might have been in these missile particularly when you see what was potentially hosted at some Iraqi munitions dumps.

I mentioned at the start of this post about how Gulf War illness is something not unfamiliar to my time in autism research. One of the questions that has been asked over the years concerns what happened to the offspring of those veterans who were conceived after their service. Did those environmental exposures (and possibly others) so detrimental to the health of many of them have any effects on their children? How about concentrations of toxic trace elements and autism as discussed by this study** by Fido and Al-Saad based in Kuwait? Relevant or not?

* Steele L. et al. Complex factors in the etiology of Gulf War Illness: wartime exposures and risk factors in veteran subgroups. Environmental Health Perspectives. September 2011.
** Fido A. & Al-Saad S. Toxic trace elements in the hair of children with autism. Autism. August 2005.