Discussion in 'Other Health News and Research' started by SilverbladeTE, Jun 8, 2015.
Interesting one. There seem to be quite a few reports of this
"Symptoms of 'aerotoxic syndrome' are said to include: Fatigue, blurred or tunnel vision, loss of balance, seizures, memory impairment, headaches, tinnitus, confusion, nausea, diarrhoea, breathing difficulties and irritation of the eyes, nose and upper airways."
classic symptoms of nerve gas poisoning...same thing
Glad to see someone making a fuss about this.
The chances are that the 17 cabin crew staff who say their health was affected by organophosphates will be those with the TT mutation in their PON1 gene.
This TT mutation makes you 40 times more sensitive to organophosphates pesticides, so these pesticides will have a far, far stronger affect on people with the TT mutation, compared to those without this mutation. More info here.
When I got my 23andme.com genotype testing results back, I found I had the TT mutation.
I'm looking at your source for that, and I'm not seeing anything about the 40x claim. Where are you getting that number from the paper?
Whoops, looks like I misquoted myself! Thanks for catching my error Valentijn.
To correct this error: although it is true to say that the TT allele of rs662 SNP on the PON1 gene makes you much more sensitive to organophosphates pesticides, it is not really correct to say that TT makes you 40 times more sensitive. Although this TT allele will likely increase your organophosphate sensitivity by a degree approaching that figure.
There are in fact other SNPs in the PON1 gene that also determine how good PON1 is at detoxifying organophosphates from your body, which thus determine your personal sensitivity to organophosphates. These various SNPs in the PON1 gene affect its detoxification ability by altering the expression of the PON1 enzyme, or altering how efficiently the PON1 enzyme can hydrolyze organophosphate metabolites.†
However, the rs662 SNP accounts for most of the variation in PON1's ability to detox organophosphates: see this paper: The correlation of paraoxonase (PON1) activity with lipid and lipoprotein levels differs with vascular disease status.
• PON1192 = PON1 Q192R = rs662.
• The organophosphate metabolite paraoxon is used to test the detoxification ability of the PON1 enzyme (this PON1 enzyme in fact gets its name from paraoxon).
What does the TT allele in the rs662 SNP of the PON1 gene mean for aerotoxic syndrome?
Aerotoxic syndrome is the name given to ill health effects thought to arise from exposure to aircraft cabin air contaminated with engine oil and other aircraft lubricant oil fumes. Organophosphates are added to lubrication oils in aircraft as antiwear agents.
The organophosphate found in aircraft lubrication oils tricresyl phosphate (TOCP), so TOCP may be a very important factor in aerotoxic syndrome. I would think that people who are 40 times weaker in terms of their PON1 organophosphate detoxification ability are going to be most affected by TOCP in the aircraft cabin air.
This study on TOCP in aircraft air is interesting:
For a group of people who think they have been affected by organophosphates and developed ill health conditions such as aerotoxic syndrome, it is possible that by genotype testing via 23andm3.com for their PON1 alleles, to find out how good the individuals in the group are at detoxifying organophosphates, this might offer proof that their illness was indeed caused by these organophosphates. This is because you would expect that on average, this group would have a much poorer than normal ability to detoxifying organophosphates, which is likely why they, but not other airline staff they work with, were affected.
In others words, in this affected group, you would expect to find a high prevalence of the TT allele of rs662, and a high prevalence of the other SNPs which lead to poorer detoxification ability. So if this group were tested by 23andm3.com and found to have a much higher prevalence of TT than you would normally expect to find by chance, then it I think it would offer some supporting proof that this group's ill health was indeed caused by their organophosphate exposure.
Yeah, but according to the initial paper quoted, which does break things down by SNP ... rs662 TT is only reducing enzyme levels to about 40% of normal. So a bit less than half of normal, versus 1/40th of normal.
And it's impossible to extract the effect of a single SNP from a study only looking at the effect of the SNPs in combination. The combined effect certainly can't be imputed to a single member of the group.
This could be bad news for UFO theorists if even airline pilots are prone to 'mass hysteria'.
Are you referring to the paper: Paraoxonase 1 (PON1) gene -108C>T and p.Q192R polymorphisms and aryl esterase activity of the enzyme in patients with dementia ?
Could you point out where it says that please.
Note that PON1 blood enzyme levels are one aspect, and the efficiency of the PON1 enzyme at performing hydrolysis is another. As I understand it, the actual ability of the PON1 enzyme to detoxify organophosphate is determined by both enzyme blood levels and enzyme hydrolysis efficiency.
Are you saying that the study quoted above which found "PON1192 largely accounting for the paraoxon hydrolysis variation" is not justified in concluding that?
I suppose Table II has the most relevant information. In the controls, "PON activity" for controls is 174.5 for QQ and 147.6 for RR. Assuming that "activity" does mean "activity" and not "levels", RR results in about 84.6% of the activity as QQ.
Agreed, and it would be nice to see more data regarding this. Especially since some of the research that I glanced at suggests that there's a trade-off regarding that SNP, where one mutation is better at dealing with one toxin, and the other mutation is better at dealing with a different toxin.
It probably is justified, but it's a very nonspecific claim to make. No absolute percentage of the gene function is being attributed to that mutation, so it's hard to make much of it, beyond "probably important, please do more research and get more data".
It would be nice to see more data. I could not really find a good articles or reviews with a clear "take home message" summary of this research which would explain how these SNPs affect an individual's organophosphate detoxification abilities.
In this post, Rich Van Konynenburg quotes a study linking rs662 mutations in PON1 to Gulf war illness.
If there is a 40-fold variation in PON1 activity from one person to the next, which is what is stated in the Medscape article I cited, you can certainly imagine that the bad detoxifiers are going to be hit so much harder from an organophosphate exposure.
And you would expect that on average, any group of people affected by organophosphate exposure is going to contain a high prevalence of these bad detoxifiers.
Though the PON1 activity in a given individual may not just be set by their PON1 alleles: for example, this study found that leptin markedly decreases plasma PON1 activity. High leptin is found in obesity.
I am not sure if there is an easy way to directly measure PON1 activity in an individual via a blood test say. That would presumably be the most reliable way of gauging a person's detoxification ability for organophosphates.
Yeah, and exposing someone to organophosphates to see how their genotype impacts their ability to process it would be "ethically complicated"
Looks like there is a simple blood test for PON1 activity: Biolab in London offer it: Biolab Medical Unit London.
Such a test might be useful in a court case trying to prove that organophosphate exposure triggered the ill health of a group of people, because as we know, there are many environmental factors, including infectious pathogens, that can trigger ill health. So it becomes hard to prove it was organophosphates, and not something else that caused the ill health.
But if you could show that the prevalence of poor PON1 activity in your group of presumed organophosphate-affected people was higher than you would expect from chance, this could act as supporting evidence for the organophosphate etiology of the illnesses in the group.
This method of proof would not really apply to a single individual, though, because there would not be enough statistical significance. And clearly even people with the highest PON1 activity might still be affected by organophosphates if the exposure dose was high enough. So that's why you can't apply this to a single case.
But if say you have regular workplace organophosphate exposure to thousands of airline cabin staff, but out of those thousands, only say a dozen get ill, you would certainly expect most or all of those dozen to have poor PON1 activity.
Do you have evidences that the PON1 is involved in cresyl-Phosphate detox process?
According to my readings, PON1 is involved in detoxifying the toxic oxon forms of thioates parent forms of OrganoP pesticides... However the Tri cresyl P (ToCP) implicated in the aircraft poisoning is activated by cytochrome P450 to the toxic cresyl saligenin P form (not the same kind of activation).
I have find nothing about the detox process of cresyl saligenin (CBDP) (, but activation by cytochrome P450 has already been studyed:
"These results confirmed the role of human P450s 1A2 and 3A4 in ToCP metabolism and demonstrated that CBDP is the metabolite responsible for the BuChE (butyrilcholinesterase) inactivation. Interindividual differences at the level of P450 1A2 and 3A4 might play an important role in the susceptibility of humans in developing neurotoxic effects, such as aerotoxic syndrome, after exposure to ToCP."
However, the detox process by PON1 and PROL had already studied once and showed no evidences to involvment in the detox process:
"The toxicant is suspected to be cresyl saligenin phosphate (CBDP), the metabolite of tri-o-cresyl phosphate (TOCP), a component of tricresyl phosphate (TCP), the antiwear additive in jet engine lubricants. Another toxic organophosphate (OP) potentially present in jet engine fumes is trimethylolpropane phosphate (TMPP).In vivo detoxification of CBDP and TMPP is a potential source of variability in susceptibility to aerotoxic syndrome. Therefore, to determine whether the human plasma catalytic bioscavengers, paraoxonase (PON-1) and prolidase (PROL), may protect against the toxicity of CBDP and TMPP, we studied the binding and reactivity of these OPs with human PON-1 and PROL. Results showed that these enzymes do not hydrolyse CBDP and TMPP. PROL is not even inhibited by these OPs. PON-1 is competitively inhibited by both OPs with inhibition constants of the order of 10–4 M for CBDP and 10–3 M for TMPP. Such affinities are several orders of magnitude higher than the concentrations encountered in poisoning by CBDP and TMPP. Furthermore, TMPP does not react with the stoichiometric OP bioscavenger, human plasma butyrylcholinesterase (BChE). Therefore, BChE does not protect against TMPP, though it does protect against CBDP.
In summary, the human plasma catalytic bioscavengers, paraoxonase and prolidase, do not provide a natural defence against CBDP and TMPP.
PON1 is generally involved in detoxification of organophosphates, but looking just now, I cannot find any direct evidence that it can detoxify tricresyl phosphate (TCP) or its metabolites, the organophosphate added to aircraft lubrication oils as an anti-wear agent.
However, this 2014 paper suggests that PON1 is likely involved:
ToCP = tri-ortho-cresyl phosphate, which is a highly toxic isomer of tricresyl phosphate. It says here that concerns about tricresyl phosphate toxicity are largely based on the tri-ortho-cresyl phosphate isomer content, and the mono-ortho-cresyl phosphate isomer content. So it is detoxification of these ortho-cresyl phosphates that would be the main interest.
So I guess it is possible that ToCP might be metabolized by the PON1 enzyme in the blood, and if this occurs, it would prevent ToCP being converted by cytochrome P450 in the liver to the neurotoxic CBDP.
But it seems that there is no direct evidence showing that PON1 can metabolize ToCP, so it is only an assumption that PON1 can detoxify ToCP.
Another issue is the point that came up in this post on the other thread: namely that polymorphisms on the PON1 gene, such as the TT allele on the rs662 SNP, may have different effects on the PON1 detoxification of different organophosphate compounds. If I understood correctly, it seems that for some organophosphates, the TT allele may make PON1 slower at detoxification; and for other organophosphates, the TT allele may make PON1 faster at detoxification.
So I don't think we can say that the TT allele on rs662 SNP of PON1 uniformly slows the detoxification of organophosphates by PON1. I think you would need to look at this on a case-by-case basis, and experimentally for the organophosphate in question how the TT allele affects its detoxification rate by PON1.
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