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Biological Monitoring Ofexposure to Nerve Agents

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Biological Monitoring Ofexposure to Nerve Agents Br J Ind Med: first published as 10.1136/oem.49.9.648 on 1 September 1992. Downloaded from 648 British Journal of Industrial Medicine 1992;49:648-653 Biological monitoring of exposure to nerve agents J Bajgar Abstract occurred; at less than 30-55%, disturbed ven- Changes in acetylcholinesterase activity in tilation and fasciculations were seen, and at blood and some organs of rats after intoxica- 15-30%, convulsions occurred. Less than 10% tion with sarin, soman, VX, and 2-dimethy- was fatal. In experiments with narcotised dogs, laminoethyl-(dimethylamido)-phosphono- the blood acetylcholinesterase activity and the fluoridate (GV), in doses of roughly 2 x LD5. ability to reactivate it with trimedoxime were given intramuscularly, were obtained from determined after intoxication by intra- published data and by experiment. The time muscular administration of the four com- course of inhibition of acetylcholinesterase in pounds. It is concluded that acetylcholines- blood, regions ofbrain, and diaphragm and the terase activity in the blood corresponds to that occurrence of signs and symptoms of poison- in the target organs and can be considered as ing (none, salivation, disturbed ventilation and an appropriate parameter for biological fasciculations, convulsions, or death) were monitoring of exposure to nerve gases. More- summarised and compared. When blood over, determination of reactivation of blood enzyme activities were 70-100% normal, no acetylcholinesterase gives more information obvious signs were seen; at 60-70%, salivation than simple determination ofenzyme activity. Military Medical Academy, 502 60 Hradec Krilov6, Nerve agents are compounds ofhigh toxicity,' one of copyright. Czechoslovakia the many reasons for their possible use as chemical J Bajgar weapons.' Others from this class of chemicals Membrane Stressogenic r%tiRec spholipids. * .. I Mutagenic r----------, | Recc,.eptors Tyrosine amino- http://oem.bmj.com/ transferase Detoxication Proteins I binding f t Corticosterone / ~~~~~IRNA ~II L-- i- Cyclic nucleotides I AChE Catecholamines, C P .-. ChE IGABA, etc t Natriuretic Neuromediato r's on October 1, 2021 by guest. Protected Water, minerals ---_- AST r.-_______ -_ ALT muscles, heart y-GT Respiratory -OPO2 4PCo2t Convulsions 7 Leucocytes ' AIP Blood flow AcP EST Haematological L_. Glucose . Liver Lactate P Acidosis Pyruvate Cl--gG, immunity Immune Energetic Figure 1 Schematicrepresentationofpossiblecomplexeffectsof organophosphate (OP) action. AST,ALT,AcP,AIP, EST, y-GT represent transaminases, phosphatases, esterases, and y-glutamyltransferase (modifiedfrom Bajgar4). Br J Ind Med: first published as 10.1136/oem.49.9.648 on 1 September 1992. Downloaded from Biological monitoring of exposure to nerve agents 649 k_, namely, sarin, soman, and VX. We have also Kd `=~ included another anticholinesterase inhibiting substance, 2-dimethylaminoethyl-(dimethylamido)- phosphonofluoridate (GV), with a similar toxicity. Figure 3 gives the formulae of the agents used. The questions arise as to whether and where the degree of AB BH AChE activity reflects the actual state ofthe organism or the degree of poisoning and whether AChE activity in blood is comparable with that in the target ka organs. k +4 Determination of simple AChE or BuChE activity EA (or inhibition) is only one indicator for the biological EA' monitoring of organophosphate action.'3 For further information on the poisoned organism and especially for its treatment, it is of interest to know if the enzyme inhibition by organophosphate can be re- versed (the enzyme can be reactivated). In some AOH cases, depending on the type oforganophosphate and on the duration of its action, the inhibited enzyme is Figure 2 Schematic representation of reaction of changed into a complex that cannot be reactivated.'2 organophosphate inhibitor (AB) with leaving group (iB) and AChE (EH). EHAB, intermediate complex; EA, This has been described as "aging".'4 The rate ofthis phosphorylated enzyme; EA', dealkylated enzyme; Kd,p aging reaction is fast for soman (minutes); AChE dissociation constant, k,, bimolecular rate constant; k,, k+,, activity inhibited by sarin is aged within hours, and k+2, k+3, and k+4, rate constants (according to Aldridgre and aging of AChE inhibited by VX was not found.""'6 Aldridge and Reiner'2). No information exists on reactivation of AChE inhibited by GV. Determination of ability to re- copyright. (organophosphorus compounds) with similar activate inhibited AChE offers another possibility for mechanisms of action-but less toxicity-aroe fre- the biological monitoring of exposure to organo- quently used as insecticides and medical druggs and phosphates. they are evaluated by industry. Some of the r*esults and conclusions from this paper could therefc re be Material and methods applied not only to nerve agents but to organolphos- EVALUATION OF PUBLISHED DATA phates in general. We used published data'5-'9 summarised in the paper The basic mechanisms of action of organoophos- by BajgarP describing the inhibition of AChE in the phates (including nerve agents) are well kncWnM13; blood and other organs of female rats after intra- http://oem.bmj.com/ they involve cholinesterase inhibition with sub- sequent accumulation of the neurotransnnitter, SOMAN SARIN acetylcholine, changes in membrane permealbility, CH3 0 CH3 0 and other metabolic imbalances. Figure 1 showrs that \ CH P CH3 P these changes are complex.4 Attempts to coIrrelate \ / \ action of nerve agents with changes in blood fIow,5 6 CH3-C-CHO F CHO F / detoxication,7 and carboxylesterase activity89 have OH3 OH3 CH3 been made. Cholinesterase activities in the blood on October 1, 2021 by guest. Protected (erythrocyte acetylcholinesterase (AChE, EC vx 3.1.1.7) and plasma butyrylcholinesterase (BuiChE, CH3 0 EC 3.1.1.8)) are the most accessible for moniitoring CH3 '1<11/P CH"I'll, the biological effects of nerve agents. The / O3 physiological importance of AChE is greaterr than C2H50 SCH2CH2N CH that of BuChE."' CH' The reaction of organophosphates with cholines- CH3 terases has been described (fig 2)." 12 It appearrs that GV the principal action (in vitro and in vivo) of organo- (CH3)2N 0 phosphates is inhibition ofcholinesterases (espe:cially AChE). .The site of the inhibition depends c)n the CH3 type of agent examined. F OCH2CH2Ns We have used previously published data describ- CH3 ing symptoms of poisoning and AChE activity in blood after intoxication with three nerve age.nts- Figure 3 Structuralformulae of the agents used. Br J Ind Med: first published as 10.1136/oem.49.9.648 on 1 September 1992. Downloaded from 650 Bajgar REACTIVATION OF AChE ACTIVITY IN VIVO DV, F C D Reactivation of blood AChE activity in vivo was described previously.22 The method is based on a duplicate determination of AChE activity with and |Soman without reactivator (trimedoxime chloride, L&eiva Praha, Czechoslovakia) at a concentration with negligible effect (5 x 10-3M) on the hydrolysis of substrate, acetylthiocholine (Lachema Brno, 10 Czechoslovakia).23 These experiments were per- 1010 formed on beagle dogs (Velaz Praha, Czechoslovakia) S DV,F C D of both sexes, weighing 8-12 kg, (n = 3-5). The dogs were anaesthetised and intoxicated by intra- muscular injection of soman (0 007 mg/kg), sarin 50 - Sarin| | (0-03 mg/kg), VX (0-003 mg/kg), or GV (0-004 mg/kg). Blood was collected at different time intervals -0 and the percentage of AChE activity or its reactiva- tion was determined. In this case, the symptoms 1I 0- 5 10 registered were only salivation and fasciculation. - L) Convulsions and death were not seen because of the 11JU 4 low doses of the agents used and modification of the |S DV, FF C D symptoms by narcotisation. 5;0 4I STATISTICAL EVALUATION AND CHEMICALS Statistical evaluation was performed with relevant VX programmes using a Turbo 12 computer. 5,5- Dithiobis-2-nitrobenzoic acid (Serva Heidelberg, Germany) was used as chromogen for AChE activity copyright. 10 20 determination. Other chemicals of analytical grade 10)OF were obtained from Lachema Brno. S DV, F C D Results 50 Figure 4 shows the changes in AChE activities in rat blood. The decrease in halflives for activity ofAChE in the materials examined (table) showed that, after http://oem.bmj.com/ soman intoxication, inhibition of AChE in the pon- 0 10 20 tomedullar area and diaphragm proceeded quickly Time (min) Figure 4 AChE activity changes in rat blood and Table Half lives of inhibition of AChE activity in vivo occurrence of symptoms ofpoisoning after intoxication with after sarin, soman, VX, or GVpoisoning the agents examined. The results are presented means only. S = salivation; DV, F = disturbed ventilation and Agent and Half lives fasciculations; C = convulsions; D = death. dose (mg/kg) Material min (95% CI) on October 1, 2021 by guest. Protected Soman: 0-154 Blood 0-7 (0 51- 0 90) Pontomedullar area 1-5 (09- 2-1) muscular administration of soman, sarin, and VX. Basal ganglia 2-8 (1 8- 3-9) The doses were roughly 2 x LD,0-namely, 0-36 Diaphragm 1-6 (09- 2-2) Sarin: mg/kg for sarin, 0-154 mg/kg for soman, and 0-030 0-360 Blood 1-08 (08- 1-4) mg/kg for VX. Pontomedullar area 1-91 (1-5- 2-4) Basal ganglia 2-7 (2-1- 3-5) Diaphragm 3-1 (28- 3-4) INHIBITION OF AChE ACTIVITY IN VIVO BY GV VX: For compound GV, female Wistar rats (Velaz Praha, 0-030 Blood 0-8 (06- 1-0) Pontomedullar area 8-5 (78- 8 2) Czechoslovakia) weighing 200-220 g were used. The Basal ganglia 17-2 (13-7-20-7) animals were divided into groups of six animals. Diaphragm 3-3 (28- 3-8) GV: After intoxication with GV in a dose roughly 0-034 Blood 1-2 (09- 1-5) 2 x LD50 (0 034 mg/kg), AChE activity in the blood, Pontomedullar area 5-1 (48- 54) of and was Basal ganglia 14-3 (13-7-15-0) regions brain, diaphragm determined Diaphragm 1-3 (09- 1-7) according to the method of Ellman et al.2" Br J Ind Med: first published as 10.1136/oem.49.9.648 on 1 September 1992.
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