Correction LETTER (ONLINE ONLY). For the letter ‘‘Reply to Blazer et al.: Flawed thor notes that the following sentences were omitted from the challenges to ‘Acetylcholinesterase inhibitors and Gulf War end of the first paragraph of the letter: ‘‘Their statements are illnesses’,’’ by Beatrice A. Golomb, which appeared in issue 33, counter to fact. They mischaracterize the evidence, employ the in- August 19, 2008, of Proc Natl Acad Sci USA (105:E53; first troduction of irrelevant material, and exemplify flaws in inference, published August 11, 2008; 10.1073͞pnas.0805246105), the au- as I will illustrate.’’ The corrected letter appears below. flaws that ‘‘limit confidence in causal inferences across AChEi LETTER classes from epidemiological studies viewed in isolation’’ (p. 4296). Moreover, when airing relative advantages of genetic/ Reply to Blazer et al.: Flawed enzyme studies, I note that those are (in contrast) ‘‘difficult challenges to ‘‘Acetylcholinesterase to ascribe to recall or reporting bias’’ (p. 4296). I agree that my conclusions differed from prior reports. It inhibitors and Gulf War illnesses’’ is true too that I considered only original evidence and not opinion or authority: the mischaracterizations of the article Blazer et al. (1) challenge my PNAS article (2) connecting throughout by Blazer et al. (1) ably illustrate why, when pri- CORRECTION acetylcholinesterase inhibitor (AChEi) exposure and Gulf mary sources are available, secondary representations of evi- War veterans’ (GWV) illness (GWI). Their statements are dence should be eschewed. counter to fact. They mischaracterize the evidence, employ the introduction of irrelevant material, and exemplify flaws in Beatrice A. Golomb* inference, as I will illustrate. Department of Medicine, University of California at San Diego, La Excess amyotrophic lateral sclerosis (ALS) in GWV was not Jolla, CA 92093-0995 represented as central to the inferences drawn (ref. 2, p. 4299); 1. Blazer D, et al. (2008) Acetylcholinesterase inhibition and Gulf War illnesses: Conclu- moreover, the ALS excess is shown by not one but three inde- sions are not supported by independent reviews of the same evidence. Proc Natl Acad Sci USA 105:E20. pendent studies (3–5) (including two in the supporting informa- 2. Golomb BA (2008) Acetylcholinesterase inhibitors and Gulf War illnesses. Proc Natl tion). Although rarity of ALS reduces power for risk factor iden- Acad Sci USA 105:4295–4300. 3. Haley RW (2003) Excess incidence of ALS in young Gulf War veterans. Neurology tification, mounting evidence supports a role for AChEi-relevant 61:750–756. exposures (pesticides, paraoxonase genotypes regulating organo- 4. Horner RD, et al. (2003) Occurrence of amyotrophic lateral sclerosis among Gulf War veterans. Neurology 61:742–749. phosphate detoxification) in sporadic ALS (6–8). While ALS 5. Coffman CJ, Horner RD, Grambow SC, Lindquist J (2005) Estimating the occurrence of remains rare and not a dominant contributor to neurological amyotrophic lateral sclerosis among Gulf War (1990–1991) veterans using capture– deaths, a significant ALS excess is still important. recapture methods. Neuroepidemiology 24:141–150. 6. Slowik A, et al. (2006) Paraoxonase-1 Q192R polymorphism and risk of sporadic Lack of EMG/NCV abnormalities ‘‘in numerous large, rep- amyotrophic lateral sclerosis. Clin Genet 69:358–359. resentative, controlled, investigations’’ of GWV (for which 7. Saeed M, et al. (2006) Paraoxonase cluster polymorphisms are associated with sporadic ALS. Neurology 67:771–776. they cite one study with 49 symptomatic veterans) is incom- 8. Morahan JM, Yu B, Trent RJ, Pamphlett R (2007) A gene-environment study of the paraoxo- patible how? No evidence suggests that EMG/NCV abnormal- nase 1 gene and pesticides in amyotrophic lateral sclerosis. Neurotoxicology 28:532–540. ities follow low-level AChEi exposure either. The assertion that the article did not ‘‘pay any attention to Author contributions: B.A.G. wrote the paper. recall bias’’ in epidemiological studies is false: I expressly The author declares no conflict of interest. stated ‘‘the results may be influenced by self-report bias’’ (p. *To whom correspondence should be addressed. E-mail: [email protected]. 4295) (subsuming recall bias) and also exposed other study © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0809123105 www.pnas.org PNAS Early Edition ͉ 1of1 Downloaded by guest on September 26, 2021 Acetylcholinesterase inhibitors and Gulf War illnesses Beatrice Alexandra Golomb* Department of Medicine, University of California, San Diego, CA 92093-0995 Communicated by Stephen F. Heinemann, Salk Institute for Biological Studies, San Diego, CA, January 15, 2008 (received for review December 5, 2006) Increasing evidence suggests excess illness in Persian Gulf War vet- exposed directly to combat or combat-related stressors. Health erans (GWV) can be explained in part by exposure of GWV to problems are common after conflicts and can arise from factors organophosphate and carbamate acetylcholinesterase inhibitors ranging from malnutrition to infectious disease, PTSD, and trau- (AChEis), including pyridostigmine bromide (PB), pesticides, and matic brain injury. Fatigue, for instance, is a sequela of many nerve agents. Evidence germane to the relation of AChEis to illness in exposures and part of the health picture after many conflicts. GWV was assessed. Many epidemiological studies reported a link However, the pattern and timecourse of symptoms in GWV are between AChEi exposure and chronic symptoms in GWV. The link is distinct. Musculoskeletal symptoms were not prominent in other buttressed by a dose–response relation of PB pill number to chronic postwar syndromes, and emergence of symptoms over several years symptoms in GWV and by a relation between avidity of AChEi (8) followed by symptom persistence (7) contrasts with some clearance and illness, based on genotypes, concentrations, and activ- conflicts where symptoms reportedly resolved over time upon ity levels of enzymes that detoxify AChEis. Triangulating evidence return. Additionally, symptom reporting is greater among Gulf- derives from studies linking occupational exposure to AChEis to deployed personnel than among those deployed elsewhere, such as chronic health symptoms that mirror those of ill GWV. Illness is again Bosnia (4). linked to lower activity of AChEi detoxifying enzymes and genotypes Many GWV were exposed to organophosphate (OP) and/or conferring less-avid AChEi detoxification. AChEi exposure satisfies carbamate acetylcholinesterase inhibitors (AChEi). (i) An esti- Hill’s presumptive criteria for causality, suggesting this exposure may mated 250,000 received the carbamate pyridostigmine bromide be causally linked to excess health problems in GWV. (PB) as a nerve agent pretreatment adjunct (9). (ii) Pesticides, prominently including carbamate and OP pesticides, were aggres- Gulf War veteran ͉ pyridostigmine ͉ pesticide ͉ sarin ͉ organophosphate sively used in an effort to control vector-borne disease, and the Department of Defense (DoD) has estimated at least 41,000 service members may have had overexposure to pesticides (10, 11). (iii) The ersian Gulf War veterans (GWV) from the 1990–1991 conflict Ϸ Phave a higher prevalence of chronic multisymptom health DoD estimates that 100,000 personnel were possibly exposed to problems than either nondeployed personnel or those deployed low levels of sarin nerve agent after the Khamisiyah munitions elsewhere. The illness profile is reflected by higher rates of most depot demolition (12) [although exposure levels and relevance are assessed symptoms with no one symptom common to all (1). sensitive to model assumptions and have been challenged (13)]. Fatigue, mood-cognitive, and musculoskeletal symptoms are often Modeling has focused on Khamisiyah, but other nerve agent exposures may have occurred (13). involved. The presumptive Centers for Disease Control and Pre- Moreover, the primary symptoms reported by ill GWV, such as MEDICAL SCIENCES vention (CDC) definition for Gulf War illness requires chronic fatigue, musculoskeletal, cognitive, gastrointestinal, sleep, and der- symptoms in two or more of those three domains (2). Similar matological problems (1, 2, 4), arise in domains governed by central proportions of GWV and nonGWV report low levels of assessed and peripheral cholinergic systems (systems affected by AChEis). symptoms, with the excess in GWV comprising those with moder- A 1999 RAND report articulated the possibility of a connection ate, severe, or multiple symptoms within a symptom category (1). between AChEis and illness in GWV, including potential mecha- Thus, the more discriminating Kansas definition for Gulf War nisms (such as cholinergic dysregulation), and outlined a research illness requires multiple or at least moderately severe symptoms in approach to confirm or refute an association (9). Chapters on OP three or more of six symptom groups, focused on fatigue/sleep, pain, and carbamate pesticides in a subsequent report extended this (14). neurological/cognitive/mood, gastrointestinal, respiratory, and skin A number of studies have been conducted along the lines proposed, problems (1). providing an opportunity for an updated assessment of the In epidemiological studies, 26–32% of personnel deployed to the evidence. Persian Gulf have chronic health problems after subtracting the fraction of nondeployed personnel with such problems (1, 3, 4). Results [This may understate the percentage affected,