Golomb et al. 10.1073/pnas.0711986105. |
Table 7. PON vs. illness in GWV
Citation | Sample | PON activity comparison | Finding | PON genetic comparison | Finding | Comment |
Haley * | 25 ill GWV, 20 age/sex/education "matched" veteran controls from prior case-control study. | Lowest quartile of PON1 Type Q arylesterase activity vs top 3 quartiles. | OR 4.5 (P=0.02) OR 9.0 (P=0.0009) for subset with "syndrome 2"† | R allele vs no R allele. | OR 3.4 (P=0.05) | Within genotype, activity was predictive. |
Mackness‡ | 152 ill UK GWV vs 152 age/sex matched controls. | 1. PON activity by hydrolysis, ill vs control. 2. PON1 concentration, ill vs control. | 1. 100 vs 215 nmol/min/ml, P<0.001 2. 75.5 vs 88.2µg/ml, P<0.00025 | R-allele/total PON-192 gene frequency, ill vs control. | 0.31R vs 0.25R (NS) | Independent of genotype, activity was predictive. |
This table briefly reviews findings from the Haley and Mackness studies examining PON activity and PON genetics in relation to Gulf War illness.
*Haley RW, Billecke S, La Du BN (1999) Association of low PON1 type Q (type A) arylesterase activity with neurologic symptom complexes in Gulf War veterans. Toxicol Appl Pharmacol 157: 227-233.
† "Syndrome 2" among three primary factor-analysis derived syndromes in Haley's analysis is the most impaired subgroup.
‡ Mackness, B, Durrington, PN & Mackness, MI (2000) Low paraoxonase in Persian Gulf War Veterans self-reporting Gulf War Syndrome. Biochem Biophys Res Commun 276: 729-33.
Table 8. Chronic symptoms in occupationally OP-exposed: Triangulating evidence
Citation | Sample | Exposure | Outcome | Finding |
Davies* | 175 persons from a phone-book sample of an agricultural area in England | Occupational OP exposure over the prior 10 years, vs not exposed | Presence/absence of 10 symptoms related to fatigue, cognition, muscle, and chemical sensitivity | OP-exposed more commonly report symptoms; and report more symptoms than non-OP exposed |
Davies* | 240 persons participating in a registry of persons concerned about a possible association of ill health to OP exposure | Sheep dip OP exposure vs non-dip OP exposure | Symptom profile on a survey | Sheep-dip exposed showed similar symptom profiles to non-dip OP-exposed persons |
Bazylewicz-Walczak† | 26 OP-exposed greenhouse workers and 25 non-neurotoxin exposed gardening workers; all female, similar age, education, drug exposures | Occupational OP exposure | World Health Organization-recommended Neurobehavioral Core Test Battery | Longer reaction times; reduced motor steadiness; increased fatigue, depression, and symptoms of CNS disturbance in OP-exposed |
This table reviews findings from outside the Gulf War setting linking OP pesticide exposure to symptoms similar to those reported by Gulf War veterans. The second Davies entry is included to show that sheep dip OPs give results similar to overall OPs; this provides context for findings cited in the following SI Table 9, linking PON genetics - as it relates to sheep dip detoxification - to illness in sheep dippers.
*Davies DR, Ahmed GM, Freer T (1999) Chronic organophosphate induced neuropsychiatric disorder (COPIND): results of two postal questionnaire surveys. J Nutr Environ Med 9: 123-134.
†Bazylewicz-Walczak B, Majczakowa W, Szymczak M (1999) Behavioral effects of occupational exposure to organophosphorous pesticides in female greenhouse planting workers. Neurotoxicology 20: 819-826.
Table 9. Odds ratios for illness case status by PON1 polymorphisms and PON1 activity in sheep dippers*
OR † | 95%C.I. | P | |
Position 192 | 0.001 | ||
QR or RR vs QQ | 2.3 | 1.5-3.4 | 0.001 |
Position 55 | 0.001 | ||
LL vs LM or MM | 1.9 | 1.3-2.9 | 0.002 |
Positions 192 and 55 | |||
QR or RR vs QQ | 1.9 | 1.2-3.0 | 0.004 |
LL vs LM or MM | 1.7 | 1.1-2.7 | 0.024 |
Position 192, adjusted for 55 and PON1 activity | 1.5 | 0.94-2.4 | Not stated |
Position 55, adjusted for 192 and PON1 activity | 1.9 | 1.2-3.0 | Not stated |
PON1 diazoxonase activity below median, adjusted for 192 and 55 | 1.8 | 1.1-2.8 | Not stated |
This table links PON genetics to illness in sheep dippers - exposed to the OP diazinon
When both positions 55 and 192 were analyzed: overall effect at 192, P=0.02; 55, P=0.045. The interaction term was not significant suggesting the effects were independent.
*Cherry N, et al. (2002) Paraoxonase (PON1) polymorphisms in farmers attributing ill health to sheep dip. Lancet 359: 763-764.
†Adjustment for age, sex, region, and date of first dipping did not affect results.
SI Text
Additional Supporting References
These are supplementary references complementing those in the manuscript, that help to support statements made in the text (often with other references); or rarely, statements relevant to but not included in the text. The references will be preceded by statements to which they are germane.
Those selected for deployment to high threat areas are healthier.
Selection to receive the anthrax vaccine was determined by whether one was to deploy to high threat areas. The vaccinated group showed markedly lower hospitalization rates across many categories - including cancer and blood disease - in the 40 days after receiving the vaccine than a comparison military group.
Sato PA, Reed RJ, Smith TC, Wang L (2002) Monitoring anthrax vaccine safety in US military service members on active duty: surveillance of 1998 hospitalizations in temporal association with anthrax immunization. Vaccine 20:2369-2374.
And indeed, this reflected better health before anthrax vaccine receipt: another analysis found that those chosen to receive this vaccine (a proxy for deployability) had lower hospitalization rates before getting the anthrax vaccine.
Institute of Medicine (2002) The Anthrax Vaccine. Is it safe? Does it work? (National Academy Press, Washington, DC). Table 6-4, p 141.
Greater number and severity of symptoms in ill GW veterans.
Hallman WK, Kipen HM, Diefenbach M, Boyd K, Kang H, Leventhal H, Wartenberg D (2003) Symptom patterns among Gulf War registry veterans. Am J Public Health 93:624-630.
Multiple studies now show that stress and psychological factors are inadequate to account for excess illness in GWV.
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PTSD rates are not systematically higher in GWV than in those deployed in other conflicts.
Marshall GM, Davis LM, Sherbourne CD (2000) (RAND, Arlington, VA).
...and PTSD rates in GWV may be comparable to those in the general population.
Wolfe J, Proctor SP, White RF, Friedman MJ (1998) Re: "Is Gulf War syndrome due to stress? The evidence reexamined". Am J Epidemiol 148:402-403.
Health problems are common following conflicts and can arise from factors ranging from malnutrition, dehydration and electrolyte imbalance to infectious diseases, trenchfoot, PTSD, and in the current Operation Iraqi Freedom conflict, traumatic brain injury.
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Symptoms in ill GWV emerged over several years...
Murphy FM, Kang H, Dalager NA, Lee KY, Allen RE, Mather SH, Kizer KW (1999) The health status of Gulf War veterans: lessons learned from the Department of Veterans Affairs Health Registry. Mil Med 164:327-331.
...followed by symptom persistence:
Ozakinci G, Hallman WK, Kipen HM (2006) Persistence of symptoms in veterans of the First Gulf War: 5-year follow-up. Environ Health Perspect 114:1553-1557.
Some studies also report significant increases in specialized outcomes with exposure to one or more AChEis, including peripheral neuropathy and widespread pain, gastrointestinal symptoms, multiple chemical sensitivity/chronic fatigue syndrome, and hospitalizations for arrhythmia [see also Cherry N, et al. (2001) Health and exposures of United Kingdom Gulf war veterans. Part II: The relation of health to exposure. Occup Environ Med 58:299-306; and Reid S, et al. (2001) Multiple chemical sensitivity and chronic fatigue syndrome in British Gulf War veterans. Am J Epidemiol 153:604-609.].
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In the U.K. Pesticide study [Davies DR, Ahmed GM, Freer T (1999) Chronic organophosphate induced neuropsychiatric disorder (COPIND): results of two postal questionnaire surveys. J Nutral Environ Med 9:123-134], in addition to cognitive impairment and reduced exercise tolerance, personality change was also commonly reported. This has also been true among ill GWV:
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Additional triangulating information is emerging from persons with OP AChEi (sarin gas) exposures following chemical agent terrorist attacks in Japan, although these exposures were perhaps complicated by other factors. Longterm problems with cognition, fatigue, and muscle - hallmark symptoms of ill GWV - have been reported.
Nishiwaki Y, Maekawa K, Ogawa Y, Asukai N, Minami M, Omae K (2001) Effects of sarin on the nervous system in rescue team staff members and police officers 3 years after the Tokyo subway sarin attack. Environ Health Perspect 109:1169-1173.
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Biological plausibility is strengthened by studies showing evidence of chronic and delayed consequences of repeated low level AChEi exposure to physiological systems - but is, in fact, not necessary to demonstrate.
Rajan TV (2001) The myth of mechanism [commentary]. The Scientist June 25, 2001:6.
ALS rates in GWV exceed the already elevated rates among military personnel more generally, and are rising.
Coffman CJ, Horner RD, Grambow SC, Lindquist J (2005) Estimating the occurrence of amyotrophic lateral sclerosis among Gulf War (1990-1991) veterans using capture-recapture methods. Neuroepidemiology 24:141-150.
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Emerging evidence has linked sporadic cases of ALS to agricultural chemicals and pesticides - with an apparent dose-response relationship.
McGuire V, et al. (1997) Occupational exposures and amyotrophic lateral sclerosis. A population-based case-control study. Am J Epidemiol 145:1076-1088.
The possible ALS connection is strengthened by evidence linking sporadic ALS cases to PON genotypes...
Slowik A, et al. (2006) Paraoxonase-1 Q192R polymorphism and risk of sporadic amyotrophic lateral sclerosis. Clin Genet 69:358-359.
...and perhaps PON-genotype/pesticide interactions.
Morahan JM, Yu B, Trent RJ, Pamphlett R (2007) A gene-environment study of the paraoxonase 1 gene and pesticides in amyotrophic lateral sclerosis. Neurotoxicology 28:532-540.
Parkinson's disease is a condition related in risk factors and mechanism to ALS - with cooccurrence reported in Guam and in some other settings.
Galasko D, Salmon D, Craig UK, Wiederholt W (2000) The clinical spectrum of Guam ALS and Parkinson-dementia complex: 1997-1999. Ann N Y Acad Sci 920:120-125.
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Parkinson's disease has also been related to pesticide exposure...
Petrovitch H, et al. (2002) Plantation work and risk of Parkinson disease in a population-based longitudinal study. Arch Neurol 59:1787-1792.
Fong C S, Cheng CW, Wu RM (2005) Pesticides exposure and genetic polymorphism of paraoxonase in the susceptibility of Parkinson's disease. Acta Neurol Taiwan 14:55-60.
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...and to PON genetic variants.
Akhmedova SN, Yakimovsky AK, Schwartz EI (2001) Paraoxonase 1 Met-Leu 54 polymorphism is associated with Parkinson's disease. J Neurol Sci 184:179-182.
Kondo I, Yamamoto M (1998) Genetic polymorphism of paraoxonase 1 (PON1) and susceptibility to Parkinson's disease. Brain Res 806:271-273.
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Recent evidence has begun to elucidate mechanisms by which low level, repeated AChEi exposure leads to changes in the nervous system of potential relevance to Gulf War veterans.
Kalra R, et al. (2002) Subclinical doses of the nerve gas sarin impair T cell responses through the autonomic nervous system. Toxicol Appl Pharmacol 184:82-87.
AChEis used clinically for Alzheimer's disease are typically acridine or piperidine AChEis. They are not of the OP and not typically of the carbamate variety.
Cummings JL (2000) Cholinesterase inhibitors: A new class of psychotropic compounds. Am J Psychiatry 157:4-15.
...and they may or may not lack potential for similar sequelae.
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