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Sarin
Adarsh Vangala
Introduction: Why Sarin?
• It is one of the most famous and widely used
agents of modern chemical warfare
– It has been involved in many recent conflicts
– We have a better understanding of its effects on
humans than other nerve agents
• It serves as good illustration of the mechanism
and effects of other nerve agents.
Introduction: Presentation Contents
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Uses of Nerve Agents
History of Sarin
Production
Mechanism
Physiological response and symptoms
Detection
Current Treatments
Nerve Agents
• Organophosphate compounds that disrupt
transmission of information in nervous system
– All act with similar mechanism
• Tabun (GA), Sarin (GB), Soman (GD), Cyclosarin
(GF), VX are examples used in chemical warfare
Smythies, Journal of the Royal Society of Medicine,
2004, 97.
Uses of Nerve Agents
• 1st synthesized nerve agent Tabun
developed by IG Farben in
Germany as insecticide in late 30s
– Toxic effects on humans discovered
when lab assistants accidentally
exposed
• Sarin and Tabun now used almost
exclusively for chemical warfare
Ivarsson, National Defence Research Establishment, 1992.
Civilian Uses of Nerve Agents
• Organophosphate
compounds very similar to
Sarin such as parathion and
chloropyrifos are still used
as pesticides in the U.S.
today
– Quickly degraded and
rendered nontoxic by
exposure to sunlight, air, etc.
Reigart, EPA, 2013, 43-55
Potential Medical Uses of
Organophosphates
• Cholinesterase
inhibitors might be
used to treat dementia
• Organophosphates
pyridostigmine and
physostigmine used to
treat neruomuscular
disease myasthenia
gravis
Ellis, J.M., 2005, J AM Osteopathic Assoc, 145-158
Flacke, W., 1973, N Engl J Med., 27-31
History of Sarin
• Sarin (C4H10FO2P) first
synthesized by German
scientist Gerhard Schrader
• part of G-series of synthetic
nerve agents developed for
use in chemical warfare by
German military
• never actually used during
WWII
Ivarsson, National Defence Research Establishment, 1992.
Sample, Guardian, 2013
Use in Warfare and terrorism
• One of several chemical agents used by Iraqi
government in 1988 Halabja attack killing over 5,000
• Most famously used by terrorist Aum Shinrikyo sect
during 1994 Matsumoto attack and 1995 Tokyo Subway
attack in Japan killing over 20 people.
Sample, Guardian, 2013
Modern Incidents
• rocket attacks on August 21st 2013 on Ghouta
area of Damascus during Syrian Civil war
claimed between 350 and 1400 lives
Sample, Guardian, 2013
Production of Sarin
• Several different methods used to synthesize
Sarin
– Many components such as isopropanol (rubbing
alcohol) are very common
– Most major precursors are heavily restricted by
Chemical Weapons Convention guidelines that
went into effect in 1997
• Can only easily be made in large quantities by
governments and militaries
Sample, Guardian, 2013
Acetylcholine
• Common neurotransmitter involved in
signaling muscle contraction.
• Acetylcholinesterase (AChE) is an enzyme that
hydrolyzes ACh into choline and acetic acid.
Pohanka, 2011, Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech
Repub., 219-230
CDC, 2007
Sarin Mechanism
• Sarin prevents the breakdown of Ach through
competitive inhibition.
• Sarin forms phosphate ester bond to serine
residue on AChe active site.
Wang, 2006, Phys. Chem. B. 7567-7573
CDC,2007
Mechanism Continued
• sarin-AChE complex undergoes irreversible
dealkylation that results in the cleavage of the
phosphonate ester bond.
– This irreversible process, called “aging”, permanently
removes the enzyme’s functionality.
Wang, 2006, Phys. Chem. B. 7567-7573
CDC, 207
Physiological response
• Sarin exposure causes buildup of ACh
• Causes uncontrollable muscle contractions
– May cause paralysis when ATP depleted
• Most of the acute symptoms observed when
75-80% of the AChE inhibited
– 1995 Tokyo subway victims showed decreased
erythrocyte cholinesterase activity 3 years after
the attack
Yanagisawa, 2006, Journal of the Neurological Sciences, 76-85
Okumura, 2005, Toxicol. Appl. Pharmacol., 471-476
Symptoms
• Symptoms of inhalation usually appear within
five minutes
– symptoms of liquid exposure generally arise much
later
– Respiratory failure was main cause of death in
1994 Matsumoto attack
• weakness and paralysis in respiratory muscles, mixes
with inhibition of the respiratory center of the CNS and
thick mucus secretions in the respiratory tract
Yanagisawa, 2006, Journal of the Neurological Sciences, 76-85
Okumura, 2005, Toxicol. Appl. Pharmacol., 471-476
Other Symptoms
• bradycardia (depressed heart rate) due to
effects on muscarine ACh receptors
• tachycardia (elevated heart rate) due to
effects on nicotinic ACh receptors
• blurred vision, headaches, and coughing.
Yanagisawa, 2006, Journal of the Neurological Sciences, 76-85
Okumura, 2005, Toxicol. Appl. Pharmacol., 471-476
Detection
• Sarin is very volatile and can be very
dangerous even in small quantities.
– Degrades quickly under environmental conditions
– Exposes workers to risk
• detection methods focus on identifying more
stable Sarin metabolites
Abu-Qare, 2002, Food and Chemical Toxicology, 1327-1333
Okumura, 2005, Toxicol. Appl. Pharmacol., 471-476
Methods of Detection
• Gas
chromatography,
mass spectrometry
identify metabolites
– Metabolites
methylphosphonic
acid (MPA) or IMPA)
isolated from soil
samples, urine of
victims, etc.
Abu-Qare, 2002, Food and Chemical Toxicology, 1327-1333
Okumura, 2005, Toxicol. Appl. Pharmacol., 471-476
Treatment
• Currently mostly focuses on alleviating
symptoms
– diazepam to treat seizure symptoms
– Atropine injections limit ACh activity in muscarine
response
– oximes injections (such as 2-pralidoxime chloride)
can reactivate AChE split sarin into easier to
metabolize fragments
• Oximes are ineffective once enzyme aging has occurred
Okumura, 2005, Toxicol. Appl. Pharmacol., 471-476.
Newmark, 2004, Arch. Nerol, 649-652.
Smythies, 2004, Journal of the Royal Society of Medicine, 32.
Reasons for use of Sarin
• Highly toxic
– The LD50 of sarin gas is 179 μg/kg in mice
• Highly volatile (mostly gas at room
temperature)
– Can be easily inhaled or absorbed through skin
• Sarin much less toxic and less stable than
other G-series nerve agents and more modern
V-series nerve gases developed by U.S.
– But manufacturing generally easier
Barriers to effective treatment
• “Aging” is nearly impossible to reverse
– Sarin-AChe complex relatively stable as well
• Sarin is quick acting and very toxic even in small
quantities
– Difficult to detect
– Victims often die before they can receive medical care
– Medical personnel in many areas not
equipped/trained to treat Sarin exposure
– Poor access to medical care in regions where Sarin
most likely to be used
Okumura, 2005, Toxicol. Appl. Pharmacol., 471-476.
Newmark, 2004, Arch. Nerol, 649-652.
Smythies, 2004, Journal of the Royal Society of Medicine, 32.
Conclusions
• Sarin is widely used in chemical warfare
– Very toxic and relatively easy to produce
• Similar organophosphates are relevant for
both chemical warfare and pesticides
• Current treatment methods are largely
ineffective
• Likely to remain relevant in future conflicts
due to effectiveness
Avenues for future research
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More effective treatments
Better protective gear
More rapid and efficient detection methods
Potential long term health effects of exposure
on cholinesterase activity
References
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Smythies, J, Golomb, B. 2004. Nerve gas antidotes. Journal of the Royal Society of Medicine. 97, 32.
Ivarsson U, Nilsson H, Santesson J, eds. 1992 A FOA briefing book on chemical weapons: threat,
effects, and protection. Umeå, National Defence Research Establishment.
Reigart, J.R. and J.R. Roberts. 2013. "Recognition and Management of Pesticide Poisonings." (6th
ed.) United States Environmental Protection Agency Publication EPA-735K-13001.
Sample, I., 2013. Sarin: the deadly history of the nerve agent used in Syria. The Guardian.
Wang, J., Gu, J., Leszczynski, J. (2006) Phosphonylation Mechanisms of Sarin and
Acetylcholinesterase: A Model DFT Study. J. Phys. Chem. B. 110, 7567-7573
CDC. 2007. Cholinesterase Inhibitors: Including Insecticides and Chemical Warfare Nerve Agents.
Agency for Toxic Substances and Disease Registry.
Yanagisawa, N., Morita, H., Nakajima, T. (2006) Sarin experience in Japan: Acute toxicity and longterm effects. Journal of the Neurological Sciences. 249(1), 76-85
Newmark, J. (2004) Therapy for Nerve Agent Poisoning. Arch. Nerol. 61(5):649-652
Okumura, T., Hisaoka, T., Yamada, A., Naito, T., Isonuma, H., Okumura, S., Miura, K., Sakurada, M.,
Maekawa, H., Ishimatsu, S., Takasu, N., Suzuki, K. (2005) The Tokyo subway sarin attack—lessons
learned. Toxicol. Appl. Pharmacol. 207, 471-476
Smythies, J, Golomb, B. (2004). Nerve gas antidotes. Journal of the Royal Society of Medicine. 97,
32.
Ellis, J.M., 2005. Cholinesterase Inhibitors in the treatment of dementia. J AM Osteopathic Assoc.
105, 145-158
Flacke, W., 1973, Treatment of Myasthenia Gravis. N Engl J Med., 288, 27-31