Sarin hydrolysis products

Y. Matsuda, M. Nagao, T. Takatori, H. Niijima, M. Nakajima, H. Iwase, M. Kobayashi and K. Iwadate, Detection of sarin hydrolysis product in formalin-fixed brain tissues of victims of the Tokyo subway terrorist attack, Toxicol. Appl Pharmacol, 150, 310-320 (1998). 

Nagao M, Takatori T, Matsuda Y, Nakajima M, Niijima H, Iwase H, Iwadate K, Amano T. Detection of sarin hydrolysis products from sarin-like organophosphorus agent-exposed human erythrocytes. J Chromatogr B, 1997a 701 9-17. 

The ester group is then hydrolysed, and the hydrolysis normally stops at the MePO(OH)2 stage. More vigorous conditions are required to rupture the Me—P bond. Thus the normal hydrolysis product of D.F.P. and of tabun, namely, phosphoric acid, will give a positive test with ammonium molybdate, whereas the product from sarin, namely, methylphosphonic acid, will not respond to this test. Vigorous reagents such as hot nitric acid and ammonium persulphate will break the C—P link and then a positive test for phosphate is obtained with ammonium molybdate. Sarin can be prepared in a variety of ways. Three... 

P. D Agostino et al., Determination of Sarin, Soman and their hydrolysis products in soil by packed capillary liquid chromatography-electrospray mass spectrometry. J. Chromatogr. A 912, 291-299 (2001)... 

Using similar LC conditions but employing a sensitive LC/TOF/MS system, the same authors analyzed sarin, soman, and their hydrolysis products in soil (11). Three representative soil types were... 

VX appears to follow a similar pathway, the major metabolite being ethyl MPA (EMPA). An additional metabolite, derived from the diisopropy-laminoethyl substituent, was identified in human plasma following an assassination with VX (45). The sulfide (17), derived from enzymatic S-methylation of the hydrolysis product HSCH2CH2N(i-Pr)2, was identified in human serum by GC/MS after simple extraction. Experiments in rats confirmed the rapid metabolic formation of (17) from HSCH2CH2N(i-Pr)2 (46). Identification of this metabolite distinguishes VX from the O-ethyl analogue of sarin. 

An alternative displacement method, reported by Nagao and coworkers (46,47), is based on a lengthy and more complex procedure. Sarin-bound acetylcholinesterase was solubilized from erythrocyte membranes, digested with trypsin (37 °C, 24 h), and the hydrolysis product isopropyl methylphos-phonic acid released by digestion with alkaline phosphatase (37 °C, 48 h). High molecular mass... 

Sarin and its corresponding nontoxic hydrolysis products (IMPA, and additional methyl phosphonic acids) are predominantly eliminated via the kidneys which are thus more important for detoxification than the liver (Little et al, 1986 Waser and Streichenberg, 1988). Urinary excretion happens quite rapidly as demonstrated for single dose s.c. application of sarin, cyclosarin, and soman to rats (Shih et al, 1994). The terminal elimination half-life was found to be 3.7 =E 0.1 h for sarin and 9.9 0.8 h for cyclosarin. In contrast soman showed a biphasic elimination with terminal half-fives of about 18.5 h and 3.6 h (Shih et al, 1994). Maximum peak levels of sarin metabolites in urine were detected 10-18 h after exposure (Minami et al, 1997) and after 2 days hydrolyzed sarin metabolites had been excreted nearly quantitatively (Shih et al, 1994). In contrast, even at 5 days post-exposure soman metabolite recovery was only 62% (Shih et al, 1994). Excretion of soman from blood, fiver, and kidney compartments following cfiemical and enzymatic hydrolysis is considered a first-order elimination process (Sweeney et al, 2006). 

The reaction of sarin with hydrogen chloride has been reported and kinetics determined by NMR imaging (Bard et al., 1970). With rate constants determined at 25°C, 81.5°C, and 100°C, Arrhenius analysis led to a calculated activation energy of 17.8 kcal/mole. The base-induced hydrolysis of sarin analogs and tabun was studied by Larsson (1958b) and the half-life of GA has been estimated to be 1.5 min at pH = 11 at 25°C. Ultimately, and depending on conditions (pH, reaction times, and so forth), hydrolysis products may include fluoride ion (or hydrogen fluoride), the 1-methylethyl ester of methylphosphonic acid, methylphosphonic acid, and 2-propanol. 

The alkyl methylphosphonic acids provide a convenient marker for determining exposure to nerve agents. Numerous modifications for the assay of these compounds have been developed for blood or urine, and several have been applied to actual human exposure cases. Important factors in considering this test are extent of exposure and time following the event. One of the most severely poisoned victims of the Matsumoto sarin attack demonstrated measurable IMPA in the urine on the seventh day. To put the severity of this case in perspective, AChE values were in the range of 5%-8% of normal (Nakajima et al., 1998). However, in most cases, hydrolysis products should not be considered to be present for more than 24-48 h following exposure. The methods used to verify human exposure to nerve agents based on assay of hydrolysis products are presented in Table 19.2. 

Large amounts of 0-isopropyl methylphosphonic acid were found in blood and nrine of victims of the terrorist attacks with sarin in Matsumoto and Tokyo. Until recently, it was assnmed that hydrolysis of phosphofluoridates in plasma and tissues of mammals proceeds exclusively by cleavage of the P F bond. For example, treatment of C( )P( )- P-soman with rat plasma or liver homogenate did not lead to any conversion of PMPA into the secondary hydrolysis product methylphosphonic acid (MPA). Ramachandran observed that the primary hydrolysis product of DF P, i.e., 0,0-diisopropyl P-phosphoric acid, is not metabolized after s.c. admiiustration to mice. Rather, the product was excreted unchanged into urine. However, Nakajima et al. reported that MPA was detected (in urine) until the third day after hospitalization of a victim of the terrorist attack with sarin in Matsumoto. This discrepancy needs further investigation. 

Nerve agent residues remaining in the natural environment are likely to undergo substantial hydrolysis in the period immediately following dissemination. In investigation of allegations of use it is therefore important to analyse for trace levels of hydrolysis products. The important hydrolysis products of sarin, soman and GF are the isopropyl, pinacolyl and cyclohexyl methylphosphonic acids, which are slowly hydrolysed further to methylphosphonic acid. VX is predominantly hydrolysed to ethyl methylphosphonic acid... 

On March 20, 1995, a terrorist attack using sarin occurred on the Tokyo subway. The sarin was mixed in organic solvent and vaporised in the closed compartment of a train. Many people inhaled the sarin gas and collapsed, Eventually, 12 people died and more than 5000 were injured (Suzuki et ah, 1995 Masuda et ai., 1995 Nozaki et ai, 1995). However, neither sarin nor its hydrolysis products were detected in the blood of almost all the sarin victims. It was concluded that sarin pa.ssed through the blood-brain barrier and became distributed in brain ti.ssuc. These facts suggest that various brain... 

We do not consider the toxicity of hydrolysis products, thus underestimating the danger. For example, in the hydrolysis of sarin, several compounds are formed, and among them only one can be considered non-toxic. In the case of yperite, hydrolysis products are also highly toxic, and, as for lewisite, oxide produced in hydrolysis is equally dangerous. 

Animal data indicate that nerve agents rapidly distribute to the brain, lungs, heart, diaphragm, kidneys, liver and plasma. The concentrations in all tissues initially decline rapidly, followed by a second more gradual decline, reflecting metabolism and urinary elimination, respectively. The measurement of the hydrolysis product of sarin [0-isopropyl methylphosphonic acid (IMPA)] in urine may be used for retrospective detection of exposure, although it is... 

This material is a degradation product from hydrolysis of VX (C01-A016) and Ethyl Sarin (C01-A005). 

The second-order rate constant for the reaction between sarin and either 2-PAM I or II was found to be 170 L/mol per minute. If a phosphorylated or phosphonylated oxime that does not enter rapidly into the second step above is formed, that product may be an Inhibitor of cholinesterase. 7,88 Hydrolysis of sarin in the presence of 200-fold concentrations of V and II took place more rapidly in plasma from rats with the former oxime than with the... 

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