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PubMed1997

Unexpected nerve gas exposure in the city of Matsumoto: report of rescue activity in the first sarin gas terrorism.

This report describes the rescue activities and the exposure of rescue and hospital personnel from the first unexpected nerve gas terrorist attack using sarin (isopropyl methylphophonofluoridate) in the city of Matsumoto at midnight on June 27, 1994. The details of the emergency activities in the disaster were studied based on the records from emergency departments of the affiliated hospitals and records from the firehouse. About 600 people, including residents and rescue staff, were exposed to sarin gas. Fifty-eight residents were admitted to hospitals, and 7 died. Among 95 rescuers and the duty doctor from the doctor car, 8 had mild symptoms of poisoning. All the rescue activity took place without gas masks or decontamination procedures. In this case of unexpected mass exposure to sarin gas, the emergency rescue system for a large disaster in Matsumoto city, which had been established for a conflagration or a local earthquake, was effective.

Humans↗
PubMed2002

Sarin causes early differential alteration and persistent overexpression in mRNAs coding for glial fibrillary acidic protein (GFAP) and vimentin genes in the central nervous system of rats.

Neurotoxic effects of single dose of 0.5 x LD50 sarin (O-isopropylmethylphosphonoflouridate) on central nervous system (CNS) of male Sprague-Dawley rats were studied. We investigated the mRNA expression of the astroglial marker genes glial fibrillary acidic protein (GFAP) and vimentin to evaluate the fate of astroglial and neuronal cells, because reactive gliosis is very often used to assess the extent of CNS damage. Rats were treated with 50 microg/kg/ml of sarin and terminated at the time-points 1 and 2 hours and 1, 3, and 7 days post-treatment. Control rats were treated with normal saline. Total RNA was extracted and Northern blots were hybridized with cDNA probes for GFAP and vimentin, as well as 28S RNA (control). The data obtained indicate that a single dose of sarin (0.5 x LD50) showed induction in the transcript levels of GFAP and vimentin in the cortex, cerebellum, brainstem and midbrain, and spinal cord. The induction showed distinct spatial-temporal differences for each tissue studied. Both GFAP and vimentin were induced at 1 hour in all the tissues studied except brainstem, where moderate and high levels of GFAP induction were noted at 1 and 3 days. Overexpressed transcript levels of GFAP and vimentin remained high in more responsive tissues such as the brainstem and midbrain. Other tissues, such as the cortex, spinal cord, and cerebellum showed a more downward trend for either GFAP or vimentin, or both, transcript levels at 7 days. It is noteworthy that both cortex (318 +/- 12%) and spinal cord (368 +/- 12%) showed relatively higher induction of GFAP, whereas cortex alone showed the highest level of overexpressed vimentin transcript levels (284 +/- 11%). Overall it is also clear that both GFAP and vimentin are needed for the effective recovery involving co-ordinated alternating up- and downregulation of these two key astrocyte genes, depending on tissue specificity. The changes seen in the transcript levels of GFAP and vimentin may be the result of astrocyte dysfunction and loss, accompanied by compensatory proliferation and dedifferentiation of the astroglia. These changes could affect the neuronal cell types, thus altering the neuron-glia homeostasis.

Animals↗
PubMed1996

The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin.

Many organophosphorus compounds (OPs) are potent cholinesterase inhibitors, accounting for their use as insecticides and, unfortunately, also as nerve agents. Each year there are approximately 3 million pesticide poisonings world-wide resulting in 220,00 deaths. In 1990, there were 1.36 million kg of chlorpyrifos, 4.67 million kg of diazinon and 1.23 million kg of ethyl parathion manufactured in the USA (data supplied by the USEPA). In addition to exposure risks during pesticide manufacturing, distribution and use, there are risks associated with the major international effort aimed at destroying the arsenals of nerve agents, including soman and sarin. The United States has pledged to destroy approximately 25,000 tons of chemical agents by the end of the decade. The high density lipoprotein (HDL)-associated enzyme paraoxonase (PON1) contributes significantly to the detoxication of several OPs (Fig. 1). The insecticides parathion, chlorpyrifos and diazinon are bioactivated to potent cholinesterase inhibitors by cytochrome P-450 systems. The resulting toxic oxon forms can be hydrolysed by PON1, which also hydrolyses the nerve agents soman and sarin (Fig. 1). PON1 is polymorphic in human populations and different individuals also express widely different levels of this enzyme. The Arg192 (R192) PON1 isoform hydrolyses paraoxon rapidly, while the Gln192 (Q191) isoform hydrolyses paraoxon slowly. Both isoforms hydrolyse chlorpyrifos-oxon and phenylacetate at approximately the same rate. The role of PON1 in OP detoxication is physiologically significant. Injected PON1 protects against OP poisoning in rodent model systems and interspecies differences in PON1 activity correlate well with observed median lethal dose (LD50) values. We report here a simple enzyme analysis that provides a clear resolution of PON1 genotypes and phenotypes allowing for a reasonable assessment of an individual's probable susceptibility or resistance to a given OP, extending earlier studies on this system. We also show that the effect of the PON1 polymorphism is reversed for the hydrolysis of diazoxon, soman and especially sarin, thus changing the view of which PON1 isoform is considered to be protective.

Aryldialkylphosphatase↗
PubMed1996

Developmental toxicity of sarin in rats and rabbits.

Sarin (Agent GB, isopropyl methylphosphonofluoridate) is an organophosphate cholinesterase inhibitor. Sarin (Type I or Type II) was administered by gavage to CD rats on d 6-15 of gestation at dose levels of 0, 100, 240, or 380 micrograms/kg/d and to New Zealand White (NZW) rabbits on d 6-19 of gestation at dose levels of 0, 5, 10, or 15 micrograms/kg/d. Females were weighed on gestational days (GD) 0, 6-16 for rats and 6-20 for rabbits, and immediately prior to termination (GD 20 for rats and GD 29 for rabbits). All animals were monitored daily for clinical signs of toxicity throughout dosing and until sacrifice. At necropsy, gravid uteri were weighed and examined for the number and status of implants (live, resorbed, or dead). Individual fetal body weight, malformations, and variations (external, visceral, and skeletal) were recorded. Rat and rabbit dams in the high-dose groups exhibited significant signs of maternal toxicity and increased maternal mortality. Examination of gravid uteri revealed no statistical differences among treatment groups in the incidence of resorptions or of dead or malformed fetuses, or in average body weight of live fetuses per litter. These results show no evidence or developmental toxicity in the CD rat or NZW rabbit following exposure to either Type I or Type II sarin during embryonic differentiation and major organogenesis, even at a dose that produced maternal toxicity.

Administration, Oral↗
PubMed2005

Acute toxicity of isopropyl methylphosphonic acid, a breakdown product of sarin, to eggs and fry of golden shiner and channel catfish.

Several countries, including the United States, have agreed to destroy stockpiled chemical warfare agents in accordance with the Chemical Weapons Convention Treaty of 1993. Sarin is one of many chemical warfare agents (CWA) designated for destruction. In the event of an accident during incineration, sarin or its decomposition products have the potential to be expelled into the environment. Sarin hydrolyzes into isopropyl methylphosphonic acid (IMPA), a compound detected in groundwater from prior CWA production. This study determined the acute toxicity of IMPA to golden shiner, Notemigonus crysoleucas, and channel catfish, Ictalurus punctatus, eggs and 15-posthatch (dph) fry. The median lethal concentration (LC50) values at time of hatch for golden shiner and channel catfish eggs were 66.6 mg/L (hatched in 72 hr) and 167.5 mg/L (hatched in 168 h) IMPA, respectively. The 96-h LC50 estimates for 15-dph golden shiner and channel catfish fry were 93.9 and 144.1 mg/L IMPA, respectively. The lowest LC50 value from the most sensitive species in this study is approximately 100 times greater than the human adult lifetime drinking water health advisory value, and is approximately 2500 times greater than the critical reporting limit (> or =0.025 mg/L) for IMPA detection in groundwater from CWA production. These results are critical in understanding the toxicological properties of this potential environmental contaminant.

Animals↗
PubMed2005

A comparison of the potency of newly developed oximes (K005, K027, K033, K048) and currently used oximes (pralidoxime, obidoxime, HI-6) to reactivate sarin-inhibited rat brain acetylcholinesterase by in vitro methods.

The potency of newly developed and currently used oximes to reactivate sarin-inhibited acetylcholinesterase was evaluated using in vitro methods. A rat brain homogenate was used as a source of acetylcholinesterase. Significant differences in reactivation potency among all tested oximes were observed. Although the ability of newly developed oximes to reactivate sarin-inhibited acetylcholinesterase does not reach the reactivating potency of the oxime HI-6, the oxime K033 seems to be a more efficacious reactivator of sarin-inhibited acetylcholinesterase than other currently available oximes (pralidoxime, obidoxime) at concentrations (10(-5)-10(-4)M) corresponding to recommended doses in vivo. The results of our study also confirm that the reactivation potency of the tested reactivators depends on many factors, such as (1) the number of pyridinium rings, (2) the number of oxime groups and their position, and (3) the length and the shape of the linkage bridge between pyridinium rings.

Acetylcholinesterase↗
PubMed1986

Acute effects of Soman, Sarin, and Tabun on cyclic nucleotide metabolism in rat striatum.

Rats were injected sc with 120 micrograms/kg Soman, 120 micrograms/kg Sarin or 240 micrograms/kg Tabun. At 15 min, 2 h, or 6 h after administration, animals were decapitated along with saline-treated controls, and striatal activities of nucleotide cyclases and phosphodiesterases and striatal cyclic nucleotide levels were determined. All three agents had two similar effects on rat striatal cyclic nucleotide systems: they all increased cyclic GMP levels 15 min after their administration, and they all decreased guanylate cyclase activity 2 h after administration. There were also some different effects elicited by these three organophosphorus compounds. Different effects of Soman and Sarin seem to be mainly due to their different potencies, which in turn influence the time course of their actions. Tabun is quite different from Soman and Sarin in several respects: it rarely causes convulsions at sub-lethal doses, it has no effects on striatal cyclic AMP levels, and it affects enzyme activities 6 h after its administration. These differences may be due to the presence of cyanide instead of fluoride in its structure: i.e., this may be responsible for the different effects of Tabun on striatal cyclic nucleotide systems, and perhaps other biochemical effects. These results also indicate that other neurotransmitter systems, in addition to the cholinergic system, may be involved in organophosphate-induced toxicity.

Adenylyl Cyclases↗
PubMed1989

Comparison of the effects of diisopropylfluorophosphate, sarin, soman, and tabun on toxicity and brain acetylcholinesterase activity in mice.

The LD50s and ED50s for inhibition of acetylcholinesterase (AChE) in whole mouse brain by DFP (diisopropylfluorophosphate), sarin (methylphosphonofluoridic acid 1-methyl ethyl ester), soman (methylphosphonofluoridic acid 1,2,2-trimethyl propyl ester), and tabun (dimethylphosphoramidocyanidic acid ethyl ester) were compared after iv administration. The LD50s of DFP, sarin, soman, and tabun in ICR (Institute for Cancer Research) mice were 3.40, 0.109, 0.042, and 0.287 mg/kg, respectively. The recovery of AChE activity in whole mouse brain after sub-LD50 doses of these agents was slow and did not reach control values by 14 d after iv administration. AChE activity was inhibited in a dose-dependent manner in whole mouse brain, as well as in six brain regions (cortex, hippocampus, striatum, midbrain, medulla-pons, and cerebellum). None of these brain areas appeared to be particularly sensitive to AChE inhibition. The ED50s for DFP, sarin, soman, and tabun for inhibition of AChE in whole mouse brain were approximately 19, 38, 69, and 66% of their respective LD50s. Because of the differential potencies between lethality and inhibition of AChE, it is concluded that the lethality of these agents is due to more factors than simply the inhibition of AChE within the brain.

Acetylcholinesterase↗
PubMed2000

Acute sarin exposure causes differential regulation of choline acetyltransferase, acetylcholinesterase, and acetylcholine receptors in the central nervous system of the rat.

Acute neurotoxic effects of sarin (O:-isopropylmethylphosphonoflouridate) in male Sprague-Dawley rats were studied. The animals were treated with intramuscular (im) injections of either 1 x LD(50) (100 microg/kg), and sacrificed at 0. 5, 1, 3, 6, 15, or 20 h after treatment, or with im injections of either 0.01, 0.1, 0.5, or 1 x LD(50) and sacrificed 15 h after treatment. Plasma butyrylcholinesterase (BChE) and brain regional acetylcholinesterase (AChE) were inhibited (45-55%) by 30 min after the LD(50) dose. BChE in the plasma and AChE in cortex, brainstem, midbrain, and cerebellum remained inhibited for up to 20 h following a single LD(50) treatment. No inhibition in plasma BChE activity was observed 20 h after treatment with doses lower than the LD(50) dose. Midbrain and brainstem seem to be most responsive to sarin treatment at lower doses, as these regions exhibited inhibition (approximately 49% and 10%, respectively) in AChE activity following 0.1 x LD(50) treatment, after 20 h. Choline acetyltransferase (ChAT) activity was increased in cortex, brainstem, and midbrain 6 h after LD(50) treatment, and the elevated enzyme activity persisted up to 20 h after treatment. Cortex ChAT activity was significantly increased following a 0.1 x LD(50) dose, whereas brainstem and midbrain did not show any effect at lower doses. Treatment with an LD(50) dose caused a biphasic response in cortical nicotinic acetylcholine receptor (nAChR) and muscarinic acetylcholine receptor (m2-mAChR) ligand binding, using [(3)H]cytisine and [(3)H]AFDX-384 as ligands for nAChR and mAChR, respectively. Decreases at 1 and 3 h and consistent increases at 6, 15, and 20 h in nAChR and m2-mAChR were observed following a single LD(50) dose. The increase in nAChR ligand binding densities was much more pronounced than in mAChR. These results suggest that a single exposure of sarin, ranging from 0.1 to 1 x LD(50), modulates the cholinergic pathways differently and thereby causes dysregulation in excitatory neurotransmission.

Acetylcholinesterase↗
PubMed2005

Acute and long-lasting cardiac changes following a single whole-body exposure to sarin vapor in rats.

Epinephrine-induced arrhythmias (EPIA) are known to be associated with local cardiac cholinergic activation. The present study examined the development of QT prolongation and the effect on EPIA of whole-body exposure of animals to a potent acetylcholine esterase inhibitor. Freely moving rats were exposed to sarin vapor (34.2 +/- 0.8 microg/liter) for 10 min. The electrocardiograms (ECG) of exposed and control animals were monitored every 2 weeks for 6 months. One and six months post exposure, rats were challenged with epinephrine under anesthesia, and the threshold for arrhythmias was determined. Approximately 35% of the intoxicated rats died within 24 h of sarin exposure. Additional occasional deaths were recorded for up to 6 months (final mortality rate of 48%). Surviving rats showed, agitation, aggression, and weight loss compared to non-exposed rats, and about 20% of them experienced sporadic convulsions. Sarin-challenged rats with severe symptoms demonstrated QT segment prolongation during the first 2-3 weeks after exposure. The EPIA that appeared at a significantly lower blood pressure in the treated group in the first month after intoxication lasted for up to 6 months. This decrease in EPIA threshold was blocked by atropine and methyl-atropine. Three months post exposure no significant changes were detected in either k(D) or B(max) values of (3)H-N-methyl scopolamine binding to heart homogenates, or in the affinity of carbamylcholine to cardiac muscarinic receptors. The increase in the vulnerability to develop arrhythmias long after accidental or terror-related organophosphate (OP) intoxication, especially under challenging conditions such as stress or intensive physical exercise, may explain the delayed mortality observed following OP exposure.

Animals↗
PubMed1982

Regeneration of cholinesterases in the stellate and normal and denervated superior cervical ganglion of the cat following inactivation by sarin.

Experiments were designed to test the hypothesis that ganglionic butyrylcholinesterase (BuChE) is derived from acetylcholinesterase (AChE). At 5 to 8 days following preganglionic denervation of the right superior cervical ganglion (SCG), cats were given sarin, 2.0 mumol/kg, i.v. At intervals of 1 h and 1, 2, 3, 6, 11, and 22 days later, they were killed, and the AChE and BuChE contents of both SCG and both stellate ganglia (StG) were assayed. The regeneration of AChE in the normal ganglia occurred in two phases: an initial rapid phase, to 25-40% of control activity in 1 day, and a slow phase, to approximately 70% of control activity in 22 days. BuChE reached approximately 85% of control activity in normal SCG and StG at 22 days. In the denervated SCG, AChE activity reached a maximum of approximately 17% of normal at 1 day, the value prior to the administration of sarin, and did not increase appreciably above this subsequently. BuChE activity in the denervated SCG reached approximately 50% of normal ganglia at 22 days. At each interval, its activity approached 55% of that of the contralateral normal SCG, the value found in the denervated SCG prior to the administration of sarin. Hence, the regeneration of BuChE appears to be independent of the presence of AChE in the neuropil. The origin of ganglionic BuChE remains obscure.

Acetylcholinesterase↗
PubMed1991

Effect of soman and sarin on phosphatidylcholine asymmetry in the electroplax from the electric eel.

Some effects of organophosphorus anticholinesterase compounds that are unrelated to cholinesterase inhibition and that are sometimes long lasting may be due to alterations at the cellular membrane level. Phosphatidylcholine exchange protein was used to assess the effects of sarin and soman on phosphatidylcholine asymmetry in the inner and outer leaflets of the plasma membrane bilayer of the electroplax. Exposure of electroplax (30 min in vitro) to soman (10(-4), 10(-6) M) or sarin (10(-4), 10(-6), 5 x 10(-9) M) increased the percentage of phosphatidylcholine in the outer monolayer of the innervated plasma membrane bilayer and decreased the percentage in the inner monolayer. These changes by sarin were observed at concentrations that produced 100% cholinesterase inhibition (10(-4), 10(-6) M) and at a concentration (5 x 10(-9) M) where no inhibition occurred, suggesting that these effects are not directly due to cholinesterase inhibition. A 1-week exposure of live eels to soman (10(-8) M) in vivo caused an increase in phosphatidylcholine labeling in the outer monolayer of the innervated and noninnervated surfaces of the electroplax. Two weeks after stopping exposure to soman, increased labeling was still observed, suggesting that this may be a long-term effect. Because the organophosphates did not increase the permeability of the electroplax, all of these changes in labeling appear to be due to a redistribution of phosphatidylcholine from the inner to the outer monolayer of the plasma membrane bilayer.

Animals↗
PubMed1998

The Tokyo subway sarin attack: disaster management, Part 3: National and international responses.

The authors report the national and international responses to the disaster produced by the Tokyo subway sarin attack. From a worldwide historical perspective, there had never been such a large-scale disaster caused by nerve gas during peacetime. Therefore, this event should be studied from various viewpoints in cooperation with members of the international community. To this end, the Japanese government should help coordinate a large-scale and detailed investigation of the Tokyo subway sarin attack, including the long-term effects of sarin. The authors also recommend that the Japanese Self Defense Forces should be used more effectively in large-scale disasters. The system of direct control of disaster management by the Japanese government could be useful in a large-scale disaster.

Disaster Planning↗
PubMed1999

The effects of acutely administered low dose sarin on cognitive behaviour and the electroencephalogram in the common marmoset.

Previous studies have suggested that administration of a clinically sign-free dose of sarin to non-human primates gives rise to subtle changes in brain electrical activity as measured by electroencephalography (EEG) several months following exposure. The functional significances of such changes are unclear. The present study monitored EEG by using implantable radiotelemetry, and also assessed the performance of complex behavioural tasks, in non-human primates for up to 15 months following exposure to a low dose of sarin. Baselines of EEG and behaviour were shown to be stable over several months in control animals. The doses of sarin administered caused erythrocyte cholinesterase inhibitions of 36.4% to 67.1%. Overall, no significant changes in EEG patterns were observed although there were increases in beta 2 amplitude which approached significance (p=0.07). No deleterious effects on performance were seen on the touchscreen mediated discrimination tasks presented from the Cambridge Neuropsychological Test Automated Battery (CANTAB). This study illustrates the validity of the approach employed and makes an important contribution to the investigation of the long-term effects of organophosphorous compounds.

Acetylcholinesterase↗
PubMed2001

Psycho-physiological effects of the terrorist sarin attack on the Tokyo subway system.

The investigation describes the follow-up of the victims of the 1995 Tokyo sarin attack who were followed by a team at the St. Luke's International Hospital. A symptom questionnaire ("St. Luke's Questionnaire") was developed and given 2, 3, and 5 years following the sarin attack. Somatic and psychological symptoms have continued for 5 years after the incident. New post-traumatic stress disorder diagnostic criteria, which include physical symptoms, were developed and applied for assessment of the outcomes. The St. Luke's cohort was also compared with other Japanese sarin attack cohorts. Interventions, including counseling, medical treatments, and support group activities, were associated with fewer symptoms among the victims.

Adult↗
PubMed2004

A comparison of the efficacy of a bispyridinium oxime--1,4-bis-(2-hydroxyiminomethylpyridinium) butane dibromide and currently used oximes to reactivate sarin, tabun or cyclosarin-inhibited acetylcholinesterase by in vitro methods.

The efficacy of a bispyridinium oxime 1,4-bis(2-hydroxyiminomethylpyridinium) butane dibromide, called K033, and of currently used oximes (pralidoxime, obidoxime, oxime HI-6), to reactivate acetylcholinesterase inhibited by various nerve agents (sarin, tabun cyclosarin) was tested by in vitro methods. The new oxime K033 was found to be a more efficacious reactivator of sarin or cyclosarin-inhibited acetylcholinesterase than pralidoxime and obidoxime but it did not reach the efficacy of oxime HI-6 in the case of the inhibition of acetylcholinesterase by sarin or cyclosarin. On the other hand, oxime K033 was more efficacious than oxime HI-6 in reactivating tabun-inhibited acetylcholinesterase. Thus, oxime K033 seems to be a relatively efficacious broad spectrum acetylcholinesterase reactivator and, therefore, could be useful if no information about the type of nerve agent used was available.

Acetylcholinesterase↗
PubMedDate not supplied

Acute behavioral toxicity of the organophosphate sarin in rats.

Three experiments were performed to determine the behavioral effects of acutely administered isopropyl methylphosphonofluoridate, sarin (61-115 micrograms/kg, SC) to male rats. Dosages of 71 micrograms/kg or greater produced conditioned flavor aversions while spontaneous locomotor activity was increased at 61 micrograms/kg and significantly decreased at dosages of 84 to 115 micrograms/kg, when compared to vehicle control levels. Significant decrements in rotorod performance were observed at 98 and 115 micrograms/kg sarin. The LD50 of sarin was determined to be 165 micrograms/kg. Behavioral alterations were thus obtained at dosages that were between 37 and 59 percent of the LD50.

Animals↗
PubMed1995

[Psychiatric symptoms following accidental exposure to sarin--a case report].

A middle aged man who inhaled sarin in a train in a subway station in Tokyo in 1995 and showed a variety of symptoms including psychiatric symptoms was reported. He experienced muscle weakness, dyspnea and unconsciousness of sudden onset immediately after exposure to sarin. Marked miosis was observed on admission. Plasma cholinesterase activity was remarkably decreased at that time. He also experienced delirium consisting of visual hallucination, insomnia and irritability at mid-night for more than seven days. These psychiatric symptoms gradually improved without any medication. To date there is no detailed description of such psychiatric symptoms in sarin poisoning.

Humans↗