Gulf War Syndrome caused by sarin gas

[dann]

Quote:

US scientists say they have discovered what caused thousands of soldiers who served in the 1991 Gulf War to fall sick with mysterious symptoms.
They have pinned the blame on the nerve agent sarin, which was released into the air when caches of Iraqi chemical weapons were bombed.
(...)
Dr Haley said the key to whether somebody fell ill was a gene known as PON1, which plays an important role in breaking down toxic chemicals in the body.
His team found veterans with a less effective version of the PON1 gene were more likely to become sick.
The latest study - largely funded by the US government - involved more than 1,000 randomly-selected American Gulf War veterans.
Sarin gas blamed for Gulf War syndrome (BBC Health, May 11, 2022)

So maybe not mass psychogenic as suggested by some studies.

[Chris_Halkides]

R W Haley, S Billecke, B N La Du"Association of low PON1 type Q (type A) arylesterase activity with neurologic symptom complexes in Gulf War veterans" Appl Pharmacol. 1999 Jun 15;157(3):227-33. doi: 10.1006/taap.1999.8703. PMID: 10373407
A portion of the abstract reads, "Moreover, low activity of the PON1 type Q (Gln192, formerly designated type A) arylesterase allozyme distinguished ill veterans from controls better than just the PON1 genotype or the activity levels of the type R (Arg192, formerly designated type B) arylesterase allozyme, total arylesterase, total paraoxonase, or butyrylcholinesterase. A history of advanced acute toxicity after taking pyridostigmine was also correlated with low PON1 type Q arylesterase activity. Type Q is the allozyme of paraoxonase/arylesterase that most efficiently hydrolyzes several organophosphates including sarin, soman, and diazinon. These findings further support the proposal that neurologic symptoms in some Gulf War veterans were caused by environmental chemical exposures."

Probably the same Dr. Haley as is mentioned in the BBC article. Sounds as if this has been a longstanding research project.

[Darat]

Wouldn't we then expect to find this syndrome (for want of a better word) in the native populations? I think we can go with the assumption that their exposure would have been longer and at a higher concentration from such bombings? Is there any research into that?

[catsmate]

Originally Posted by Darat

Wouldn't we then expect to find this syndrome (for want of a better word) in the native populations? I think we can go with the assumption that their exposure would have been longer and at a higher concentration from such bombings? Is there any research into that?

Indeed. Diesel contaminated water is more likely.

[dann]

Originally Posted by Darat

Wouldn't we then expect to find this syndrome (for want of a better word) in the native populations? I think we can go with the assumption that their exposure would have been longer and at a higher concentration from such bombings? Is there any research into that?

There should be, but ... probably not.

[Planigale]

Originally Posted by Chris_Halkides

R W Haley, S Billecke, B N La Du"Association of low PON1 type Q (type A) arylesterase activity with neurologic symptom complexes in Gulf War veterans" Appl Pharmacol. 1999 Jun 15;157(3):227-33. doi: 10.1006/taap.1999.8703. PMID: 10373407
A portion of the abstract reads, "Moreover, low activity of the PON1 type Q (Gln192, formerly designated type A) arylesterase allozyme distinguished ill veterans from controls better than just the PON1 genotype or the activity levels of the type R (Arg192, formerly designated type B) arylesterase allozyme, total arylesterase, total paraoxonase, or butyrylcholinesterase. A history of advanced acute toxicity after taking pyridostigmine was also correlated with low PON1 type Q arylesterase activity. Type Q is the allozyme of paraoxonase/arylesterase that most efficiently hydrolyzes several organophosphates including sarin, soman, and diazinon. These findings further support the proposal that neurologic symptoms in some Gulf War veterans were caused by environmental chemical exposures."

Probably the same Dr. Haley as is mentioned in the BBC article. Sounds as if this has been a longstanding research project.

Actually the correct paper is

Evaluation of a Gene–Environment Interaction of PON1 and Low-Level Nerve Agent Exposure with Gulf War Illness: A Prevalence Case–Control Study Drawn from the U.S. Military Health Survey’s National Population Sample

Robert W. Haley, Gerald Kramer, Junhui Xiao, Jill A. Dever, and John F. Teiber
Published:11 May 2022CID: 057001https://doi.org/10.1289/EHP9009

Quote:

Abstract
Background:
Consensus on the etiology of 1991 Gulf War illness (GWI) has been limited by lack of objective individual-level environmental exposure information and assumed recall bias.

Objectives:
We investigated a prestated hypothesis of the association of GWI with a gene–environment (GxE) interaction of the paraoxonase-1 (PON1) Q192R polymorphism and low-level nerve agent exposure.

Methods:
A prevalence sample of 508 GWI cases and 508 nonpaired controls was drawn from the 8,020 participants in the U.S. Military Health Survey, a representative sample survey of military veterans who served during the Gulf War. The PON1 Q192R genotype was measured by real-time polymerase chain reaction (RT-PCR), and the serum Q and R isoenzyme activity levels were measured with PON1-specific substrates. Low-level nerve agent exposure was estimated by survey questions on having heard nerve agent alarms during deployment.

Results:
The GxE interaction of the Q192R genotype and hearing alarms was strongly associated with GWI on both the multiplicative [prevalence odds ratio (POR) of the interaction=3.41; 95% confidence interval (CI): 1.20, 9.72] and additive (synergy index=4.71; 95% CI: 1.82, 12.19) scales, adjusted for measured confounders. The Q192R genotype and the alarms variable were independent (adjusted POR in the controls=1.18; 95% CI: 0.81, 1.73; p=0.35), and the associations of GWI with the number of R alleles and quartiles of Q isoenzyme were monotonic. The adjusted relative excess risk due to interaction (aRERI) was 7.69 (95% CI: 2.71, 19.13). Substituting Q isoenzyme activity for the genotype in the analyses corroborated the findings. Sensitivity analyses suggested that recall bias had forced the estimate of the GxE interaction toward the null and that unmeasured confounding is unlikely to account for the findings. We found a GxE interaction involving the Q-correlated PON1 diazoxonase activity and a weak possible GxE involving the Khamisiyah plume model, but none involving the PON1 R isoenzyme activity, arylesterase activity, paraoxonase activity, butyrylcholinesterase genotypes or enzyme activity, or pyridostigmine.

Discussion:
Given gene–environment independence and monotonicity, the unconfounded aRERI>0 supports a mechanistic interaction. Together with the direct evidence of exposure to fallout from bombing of chemical weapon storage facilities and the extensive toxicologic evidence of biochemical protection from organophosphates by the Q isoenzyme, the findings provide strong evidence for an etiologic role of low-level nerve agent in GWI. https://doi.org/10.1289/EHP9009

[Planigale]

Originally Posted by Darat

Wouldn't we then expect to find this syndrome (for want of a better word) in the native populations? I think we can go with the assumption that their exposure would have been longer and at a higher concentration from such bombings? Is there any research into that?

The wind blew the plume of sarin from the bombings onto the encamped US army. Yes some natives would be affected, but Allah effectively targeted the US army keeping the Iraqis (and Iranians) safe! I do wonder if the use of pyridostigmine as an antidote which would correlate with nerve gas alarms may also be an issue.

[Planigale]

Originally Posted by catsmate

Indeed. Diesel contaminated water is more likely.

The paper is very convincing. No, diesel contaminated water would not be more likely. The strength of exposure to sarin as measured by number of nerve gas alarms and the genetic polymorphism for metabolising sarin gas both correlate with risk of GWI. Exposure to e.g. diesel fumes does not work. Another gene associated with the one they looked at, or another exposure correlated with sarin gas exposure (such as the antidote) might be an alternative explanation.

[Chris_Halkides]

Originally Posted by Planigale

Actually the correct paper is

Evaluation of a Gene–Environment Interaction of PON1 and Low-Level Nerve Agent Exposure with Gulf War Illness: A Prevalence Case–Control Study Drawn from the U.S. Military Health Survey’s National Population Sample

Robert W. Haley, Gerald Kramer, Junhui Xiao, Jill A. Dever, and John F. Teiber
Published:11 May 2022CID: 057001https://doi.org/10.1289/EHP9009

Hi Planigale,

The paper you cited is undoubtedly the paper upon which the BBC article was based. My point was that one of the authors (Haley) has been studying this topic for a long time, and the 1999 paper specifically discusses PON1. In fact they 2022 paper cites both this 1999 paper and several others, including one from 2001:
La Du BN, Billecke S, Hsu C, Haley RW, Broomfield CA. 2001. Serum paraoxonase (PON1) isozymes: the quantitative analysis of isozymes affecting individual sensitivity to environmental chemicals. Drug Metab Dispos 29(4 Pt 2):566–569, PMID: 11259353.

[Planigale]

Originally Posted by Chris_Halkides

Hi Planigale,

The paper you cited is undoubtedly the paper upon which the BBC article was based. My point was that one of the authors (Haley) has been studying this topic for a long time, and the 1999 paper specifically discusses PON1. In fact they 2022 paper cites both this 1999 paper and several others, including one from 2001:
La Du BN, Billecke S, Hsu C, Haley RW, Broomfield CA. 2001. Serum paraoxonase (PON1) isozymes: the quantitative analysis of isozymes affecting individual sensitivity to environmental chemicals. Drug Metab Dispos 29(4 Pt 2):566–569, PMID: 11259353.

Sorry misunderstood your post. You are completely correct in your comment.

[Roger Ramjets]

Originally Posted by dann

So maybe not mass psychogenic as suggested by some studies.

Quote:

However, as GWS affects approximately a quarter of subjects deployed, it is not very likely that all these symptoms are caused by a psychotraumatic reaction. Many veterans suffering from GWS have themselves rejected the diagnosis of PTSD, arguing that they do not suffer repetition nightmares...

Yet, scientific studies relating to GWS are struggling to establish opposition or continuity links between the objective external exposure (smoke from petrol wells, impoverished uranium, biological agents, chemicals) and the share of inner emotion albeit reactive and characterised by a subjective stress.

Not struggling any more...

The problem with situations like this is that symptoms can have a variety of causes, so it can be hard to identify a cause that is out of the ordinary. Soldiers have suffered from PTSD in all wars. In this case however, the unusually high incidence and symptom anomalies suggested something out of the ordinary was responsible for a large proportion. Also - unlike some cases of mass psychosis - there were plenty of potential physical causes, one of which was itself out of the ordinary.

Ironical that one of the fears in the Iraq War was that Saddam might gas us, when in reality we had already done it to ourselves!

[Planigale]

I think that one issue is that there will be gulf war syndromes. One syndrome seems to be minor* brain damage from low level exposure to nerve gas (biologically nerve gases are very similar to pesticides, just with specificity for humans vs insects). Interestingly peripheral nerve damage seems not to be an issue.

PTSD will be a different syndrome. Of course one person might have both.


*Accepting that this is not minor to the person concerned, but just in the physical extent of damage as compared with e.g. a bullet.

[Chris_Halkides]

Here is a link to another story on this subject.

"Sarin is a toxic man-made nerve agent, first developed as a pesticide, that has been used in chemical warfare; its production was banned in 1997. When people are exposed to either the liquid or gas form, sarin enters the body through the skin or breathing and attacks the nervous system. High-level sarin often results in death, but studies on survivors have revealed that lower-level sarin exposure can lead to long-term impairment of brain function. The U.S. military has confirmed that chemical agents, including sarin, were detected in Iraq during the Gulf War. In particular, satellite imagery documented a large debris cloud rising from an Iraqi chemical weapons storage site bombed by U.S. and coalition aircraft and transiting over U.S. ground troop positions where it set off thousands of nerve gas alarms and was confirmed to contain sarin."

From Dr. Haley's 2022 paper: "Two methods of mass spectrometry have been used to detect DU in human urine samples: lower precision sector-field mass spectrometry (SF-ICP-MS) has been used to differentiate DU from NU in Gulf War veterans at 238U/235U ratios above 166; whereas, higher precision multi-collector mass spectrometry (MC-ICP-MS) applied to chemically purified U can detect DU at 238U/235U ratios as low as 140." Inductively coupled plasma mass spectrometry is only somewhat familiar to me, but this link might be helpful in getting the essence of it. IIUC this paper rules out depleted uranium (DU) as a possible cause of Gulf War Syndrome
EDT
I just found a 2018 review article on paraoxonase. "Robust studies are required to clarify the clinical relevance of PON1." This story just keeps getting more complex.

[autumn1971]

Originally Posted by Roger Ramjets

Not struggling any more...

The problem with situations like this is that symptoms can have a variety of causes, so it can be hard to identify a cause that is out of the ordinary. Soldiers have suffered from PTSD in all wars. In this case however, the unusually high incidence and symptom anomalies suggested something out of the ordinary was responsible for a large proportion. Also - unlike some cases of mass psychosis - there were plenty of potential physical causes, one of which was itself out of the ordinary.

Ironical that one of the fears in the Iraq War was that Saddam might gas us, when in reality we had already done it to ourselves!

Wonder who sold him the sarin, or the information on how to manufacture it?
(Probably the US)

[Planigale]

Originally Posted by autumn1971

Wonder who sold him the sarin, or the information on how to manufacture it?
(Probably the US)

This is one you cannot blame on the US. Nerve gas manufacture is similar to making pesticides (which was the origin of nerve gases), the chemistry is well understood. It was essentially an indigenous process with precursor chemicals imported. If anyone is to blame it is probably German and Italian companies.

https://nuke.fas.org/guide/iraq/cw/az120103.html