Editing Edgewood Arsenal human experiments (section)

=== Acetylcholine related experiments ===
Much of the experimentation at Edgewood Arsenal surrounded the modulation of acetylcholine or acetylcholinesterase, or the deactivation and reactivation of substances which did the same.<ref name=":0" /> These experiments represented a significant enough proportion of the total experimentation to earn a dedicated volume in the main experimental documentation. Much of the follow up data on the acetylcholine related experiments are lacking or entirely missing, due to a combination of remaining classification and failures on the part of the [[United States Department of Veterans Affairs]] and [[United States Department of Defense]] to follow the subjects of the experimentation.<ref name=":3" />

==== Anticholinesterase experiments ====
[[Anticholinesterase]]s are substances that interfere with the [[central nervous system]] and the [[peripheral nervous system]] by inhibiting [[acetylcholinesterase]] and therefore sustaining the effect of [[acetylcholine]] or [[butyrylcholine]] within the [[chemical synapse]]s,<ref>{{Cite journal |last1=Colovic |first1=Mirjana B. |last2=Krstic |first2=Danijela Z. |last3=Lazarevic-Pasti |first3=Tamara D. |last4=Bondzic |first4=Aleksandra M. |last5=Vasic |first5=Vesna M. |date=2013-04-01 |title=Acetylcholinesterase Inhibitors: Pharmacology and Toxicology |url=https://www.eurekaselect.com/article/50871 |journal=Current Neuropharmacology |volume=11 |issue=3 |pages=315–335 |doi=10.2174/1570159x11311030006 |issn=1570-159X |pmc=3648782 |pmid=24179466}}</ref> resulting in a [[cholinergic crisis]], and possibly death if untreated.<ref>{{Cite book |title=Current therapy of trauma and surgical critical care |date=2016 |publisher=Elsevier |isbn=978-0-323-07980-8 |editor-last=Asenio |editor-first=Juan A. |edition=2nd |location=Philadelphia |editor-last2=Trunkey |editor-first2=Donald D.}}</ref>

Long term side effects of exposure to [[anticholinesterase]]s, including at levels below the threshold for profound illness and death can include paralysis and [[peripheral neuropathy]],<ref>{{Cite journal |last=Morgan |first=John P. |date=1978-08-01 |title=Jamaica Ginger Paralysis |url=http://dx.doi.org/10.1001/archneur.1978.00500320050011 |journal=Archives of Neurology |volume=35 |issue=8 |pages=530–532 |doi=10.1001/archneur.1978.00500320050011 |pmid=666613 |issn=0003-9942}}</ref> [[sleep disturbance]],<ref>{{Cite journal |last1=Metcalf |first1=David R. |last2=Holmes |first2=Joseph H. |date=June 1969 |title=EEG, PSYCHOLOGICAL, AND NEUROLOGICAL ALTERATIONS IN HUMANS WITH ORGANOPHOSPHORUS EXPOSURE* |url=http://dx.doi.org/10.1111/j.1749-6632.1969.tb15857.x |journal=Annals of the New York Academy of Sciences |volume=160 |issue=1 |pages=357–365 |doi=10.1111/j.1749-6632.1969.tb15857.x |pmid=5257403 |bibcode=1969NYASA.160..357M |issn=0077-8923}}</ref> genetic mutation and cancer.<ref name=":0" /> In total, 1,406 subjects were tested with 16 agents, some of which included reactivating agents and protective agents.<ref name=":0" />

==== Anticholinergic experiments ====
[[Anticholinergic]]s are substances that interfere with the [[central nervous system]] and the [[peripheral nervous system]] by inhibiting [[acetylcholine]], resulting in what is essentially the opposite effect of an [[cholinesterase inhibitor]] to the extreme.<ref>{{Citation |last1=Sanders |first1=Kenton M. |title=Organization and Electrophysiology of Interstitial Cells of Cajal and Smooth Muscle Cells in the Gastrointestinal Tract |date=2012 |work=Physiology of the Gastrointestinal Tract |pages=511–556 |url=http://dx.doi.org/10.1016/b978-0-12-382026-6.00018-x |access-date=2024-09-15 |publisher=Elsevier |isbn=978-0-12-382026-6 |last2=Koh |first2=Sang Don |last3=Ward |first3=Sean M.|doi=10.1016/b978-0-12-382026-6.00018-x }}</ref> This can result in anticholinergic syndrome, and possibly death if untreated.<ref>{{Citation |last1=Marx |first1=John A. |title=Dedication |date=2010 |work=Rosen's Emergency Medicine – Concepts and Clinical Practice |pages=v |url=http://dx.doi.org/10.1016/b978-0-323-05472-0.00205-x |access-date=2024-09-15 |publisher=Elsevier |isbn=978-0-323-05472-0 |last2=Hockberger |first2=Robert S. |last3=Walls |first3=Ron M.|doi=10.1016/b978-0-323-05472-0.00205-x }}</ref><ref>{{Cite journal |last=Wilson |first=T. R. |date=September 1973 |title=Belladonna alkaloids and synthetic anticholinergics. Uses and toxicity. |url=http://dx.doi.org/10.1192/bjp.123.3.366-a |journal=British Journal of Psychiatry |volume=123 |issue=574 |pages=366–367 |doi=10.1192/bjp.123.3.366-a |issn=0007-1250}}</ref>

Available data from both experiment patients<ref name=":0" /> and pharmaceutical research indicates that short-term exposure to anticholinergic compounds, especially the extremely limited exposures described in the documentation is associated with no long-term effects. It is important to note however, that in the decades since their introduction to medical use, research has begun to suggest a causal relationship between long term anticholinergic drug use and later development or worsening of [[dementia]].<ref>{{Cite journal |last1=Dmochowski |first1=Roger R. |last2=Thai |first2=Sydney |last3=Iglay |first3=Kristy |last4=Enemchukwu |first4=Ekene |last5=Tee |first5=Silvia |last6=Varano |first6=Susann |last7=Girman |first7=Cynthia |last8=Radican |first8=Larry |last9=Mudd |first9=Paul N. |last10=Poole |first10=Charles |date=January 2021 |title=Increased risk of incident dementia following use of anticholinergic agents: A systematic literature review and meta-analysis |journal=Neurourology and Urodynamics |language=en |volume=40 |issue=1 |pages=28–37 |doi=10.1002/nau.24536 |issn=0733-2467 |pmc=7821204 |pmid=33098213}}</ref> In total, 1,752 subjects were tested with 21 agents, some of whom received exposure to more than one chemical agent.<ref name=":0" />

==== Cholinesterase reactivator experiments ====
[[Pralidoxime|Cholinesterase reactivators]] are substances which reactivate [[acetylcholinesterase]] which has been inactivated by an [[anticholinesterase]].<ref>{{Cite journal |last1=Jokanović |first1=Milan |last2=Stojiljković |first2=Miloš P. |date=December 2006 |title=Current understanding of the application of pyridinium oximes as cholinesterase reactivators in treatment of organophosphate poisoning |url=https://linkinghub.elsevier.com/retrieve/pii/S0014299906010818 |journal=European Journal of Pharmacology |language=en |volume=553 |issue=1–3 |pages=10–17 |doi=10.1016/j.ejphar.2006.09.054|pmid=17109842 }}</ref><ref name=":0" /> This action can be precipitated through a variety of mechanisms, including directly binding and deactivating the anticholinesterase itself,<ref>{{Cite journal |last1=Hackley |first1=B.E. |last2=Steinberg |first2=G.M. |last3=Lamb |first3=J.C. |date=January 1959 |title=Formation of potent inhibitors of AChE by reaction of pyridinaldoximes with isopropyl methylphosphonofluoridate (GB) |url=http://dx.doi.org/10.1016/0003-9861(59)90359-5 |journal=Archives of Biochemistry and Biophysics |volume=80 |issue=1 |pages=211–214 |doi=10.1016/0003-9861(59)90359-5 |issn=0003-9861}}</ref> blocking the reaction between the anticholinesterase and the acetylcholinesterase,<ref>{{Cite journal |last=Scaife |first=J. F. |date=1960-03-01 |title=Protection of Human Red Cell Cholinesterase Against Inhibition by Tabun and O,O-Diethyl-S-2-Diethylaminoethyl Phosphorothiolate |url=http://dx.doi.org/10.1139/o60-033 |journal=Canadian Journal of Biochemistry and Physiology |volume=38 |issue=3 |pages=301–303 |doi=10.1139/o60-033 |issn=0576-5544}}</ref> changing the release of acetylcholine,<ref>{{Cite journal |last1=Sánchez-Pastor |first1=Enrique |last2=Trujillo |first2=Xóchitl |last3=Huerta |first3=Miguel |last4=Andrade |first4=Felipa |date=2007-01-31 |title=Effects of Cannabinoids on Synaptic Transmission in the Frog Neuromuscular Junction |url=http://dx.doi.org/10.1124/jpet.106.116319 |journal=Journal of Pharmacology and Experimental Therapeutics |volume=321 |issue=2 |pages=439–445 |doi=10.1124/jpet.106.116319 |pmid=17267583 |issn=0022-3565}}</ref> blocking acetylcholine's cholinolytic effect,<ref>{{Cite journal |last1=Bethe |first1=K. |last2=Erdmann |first2=W.D. |last3=Lendle |first3=L. |last4=Schmidt |first4=G. |date=1957 |title=Spezifische Antidot-Behandlung bei protrahierter Vergiftung mit Alkylphosphaten (Paraoxon, Parathion, DFP) und Eserin an Meerschweinchen |url=http://dx.doi.org/10.1007/bf00246123 |journal=Naunyn-Schmiedebergs Archiv for Experimentelle Pathologie und Pharmakologie |volume=231 |issue=1 |doi=10.1007/bf00246123 |issn=0028-1298}}</ref> or by increasing the excretion of the anticholinesterase.<ref>{{Cite journal |last1=Heilbronn |first1=E. |last2=Appelgren |first2=I.-E. |last3=Sundwall |first3=A. |date=August 1964 |title=The fate of Tabun in atropine and atropine-oxime treated rats and mice |url=http://dx.doi.org/10.1016/0006-2952(64)90120-0 |journal=Biochemical Pharmacology |volume=13 |issue=8 |pages=1189–1195 |doi=10.1016/0006-2952(64)90120-0 |pmid=14222516 |issn=0006-2952}}</ref>

Available data from the experiments<ref name=":0" /> and from prescribing information<ref name=":1">{{Cite web |title=TNAA Atropine and Pralidoxime Chloride Auto-Injector – Full Prescribing Information |url=https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/596c7a8f-27cd-4de2-9491-476f43570b8b/spl-doc?hl=pralidoxime%20chloride |access-date= |website=FDALabel Version 2.9 |publisher=Meridian Medical Technologies, LLC}}</ref> from modern marketing of these substances concludes that little risk exists of long term effects from exposure. It is noted, however, in both the prescribing information for modern variants and in toxicological research on the subject that it has been the subject of insufficient research to conclude this beyond a reasonable doubt.<ref>{{Cite journal |last1=Voicu |first1=Victor |last2=Rădulescu |first2=Flavian Ştefan |last3=Medvedovici |first3=Andrei |date=Jan 2013 |title=Toxicological considerations of acetylcholinesterase reactivators |url=http://www.tandfonline.com/doi/full/10.1517/17425255.2013.736489 |journal=Expert Opinion on Drug Metabolism & Toxicology |language=en |volume=9 |issue=1 |pages=31–50 |doi=10.1517/17425255.2013.736489 |pmid=23176543 |issn=1742-5255}}</ref><ref name=":1" /> In total, 219 subjects were tested with 4 agents.<ref name=":0" />