Elsevier

Toxicology

Volume 57, Issue 3, August 1989, Pages 241-254
Toxicology

Variability in soman toxicity in the rat: Correlation with biochemical and behavioral measures

https://doi.org/10.1016/0300-483X(89)90114-5Get rights and content

Abstract

The inhibition of cholinesterase (ChE) activity in the central nervous system of the rat by the potent organophosphorus compound soman was examined. At soman does greater than 55 μg/kg s.c. (0.5 LD50), there were: (1) dose-related inhibition of ChE activity in brain regions; (2) variability in the degree of ChE inhibition at each soman dose in each brain region; and (3) variability in the severity of signs of intoxication at each dose. These data suggest that measurements of ChE should be made directly or predicted individually in each animal for which the effects of soman are assessed. At the estimated ED50 soman dose for signs of intoxication (66 μg/kg s.c.), the remaining ChE activity in brain correlated poorly with ChE activity in plasma and red blood cells (R = 0.14−0.20), moderately with behavioral scores based on overt signs of intoxication (R = 0.63−0.94), and wellwith spinal cord ChE activity (R = 0.93−0.98). Finally, ChE activity in the thoracic and lumbosacral regions of spinal cord were not affected by head- focused microwave inactivation of brain enzymes, demonstrating that ChE activity in these regions of the cord can be used to predict the level of ChE inhibition in brain when direct measurement in brain is unfeasible.

References (27)

  • G.B. Koelle

    Cytological distribution and physiological function of cholinesterases

  • P. Taylor

    Anticholinesterase agents

  • A.G. Karczmar

    History of the research with anticholinesterase agents

  • Cited by (45)

    • Organophosphate nerve agents

      2020, Handbook of Toxicology of Chemical Warfare Agents
    • LY293558 prevents soman-induced pathophysiological alterations in the basolateral amygdala and the development of anxiety

      2015, Neuropharmacology
      Citation Excerpt :

      All animal experiments were conducted following the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, National Research Council), and were approved by the U.S. Army Medical Research Institute of Chemical Defense and the Uniformed Services University of the Health Sciences Institutional Animal Care and Use Committees, who are accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. Soman (pinacolyl methylphosphonofluoridate; obtained from the U.S. Army Edgewood Chemical Biological Center, Aberdeen Proving Ground, MD, USA) was diluted in cold saline and administered via a single subcutaneous injection (132 μg/kg, which is approximately 1.2 × LD50; Apland et al., 2013; Figueiredo et al., 2011a, 2011b; Jimmerson et al., 1989) to 111 rats. Following exposure to soman, rats were monitored for signs of seizure onset, and continuously rated for seizure severity according to the modified Racine scale (Apland et al., 2010; Racine et al., 1977; Racine, 1972): Stage 0, no behavioral response; Stage 1, behavioral arrest, orofacial movements, chewing; Stage 2, head nodding/myoclonus; Stage 3, unilateral/bilateral forelimb clonus without rearing, straub tail, extended body posture; Stage 4, bilateral forelimb clonus plus rearing; Stage 5, rearing and falling; Stage 6, full tonic seizures.

    • Organophosphate Nerve Agents

      2015, Handbook of Toxicology of Chemical Warfare Agents: Second Edition
    • Pathophysiological mechanisms underlying increased anxiety after soman exposure: Reduced GABAergic inhibition in the basolateral amygdala

      2014, NeuroToxicology
      Citation Excerpt :

      All animal experiments were conducted following the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, National Research Council), and were approved by the U.S. Army Medical Research Institute of Chemical Defense and the Uniformed Services University of the Health Sciences Institutional Animal Care and Use Committees. Soman (pinacoyl methylphosphonofluoridate) obtained from Edgewood Chemical Biological Center (Aberdeen Proving Ground, MD, USA) was diluted in cold saline and administered, via a single subcutaneous injection (149 μg/kg, which is an approximate dose of 1.35 × LD50; Figueiredo et al., 2011; Jimmerson et al., 1989), to 78 rats. Rats were monitored for signs of seizure onset (on the average, SE was initiated 5.76 ± 1.37 min after exposure), and continuously rated for seizure severity according to the modified Racine Scale: Stage 0, no behavioral response; Stage 1, behavioral arrest, orofacial movements, chewing; Stage 2, head nodding/myoclonus; Stage 3, unilateral/bilateral forelimb clonus without rearing, straub tail, extended body posture; Stage 4, bilateral forelimb clonus plus rearing; Stage 5, rearing and falling; Stage 6, full tonic seizures (Apland et al., 2010; Racine et al., 1977; Racine, 1972).

    • The recovery of acetylcholinesterase activity and the progression of neuropathological and pathophysiological alterations in the rat basolateral amygdala after soman-induced status epilepticus: Relation to anxiety-like behavior

      2014, Neuropharmacology
      Citation Excerpt :

      All animal experiments were conducted following the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, National Research Council), and were approved by the U.S. Army Medical Research Institute of Chemical Defense and the Uniformed Services University of the Health Sciences Institutional Animal Care and Use Committees. Soman (pinacoyl methylphosphonofluoridate; obtained from Edgewood Chemical Biological Center, Aberdeen Proving Ground, MD, USA) was diluted in cold saline and administered via a single subcutaneous injection (154 μg/kg), which, based on previous studies, is an approximate dose of 1.4 × LD50 (Figueiredo et al., 2011a; Jimmerson et al., 1989). Following exposure to soman, rats were monitored for signs of seizure onset, and continuously rated for seizure severity according to the modified Racine Scale: Stage 0, no behavioral response; Stage 1, behavioral arrest, orofacial movements, chewing; Stage 2, head nodding/myoclonus; Stage 3, unilateral/bilateral forelimb clonus without rearing, straub tail, extended body posture; Stage 4, bilateral forelimb clonus plus rearing; Stage 5, rearing and falling; Stage 6, full tonic seizures (Racine et al., 1977; Racine, 1972).

    • Prediction of soman-induced cerebral damage by distortion product otoacoustic emissions

      2010, Toxicology
      Citation Excerpt :

      This also explains why, in our present and previous studies (Job et al., 2007) no difference in whole blood inhibition was ever detected between C+ and C− rats. Indeed, whole blood and plasma ChE activities are most often considered as an index of exposure to ChE inhibitors rather than as an index of central toxicity for which red blood cell AChE would have provided a better indicator (Lotti, 1995; Jimmerson et al., 1989; Young et al., 2001). Confirming other studies (Job et al., 2007 and refs therein), brain ChE inhibition induced by soman 4 h after intoxication was well correlated to the symptom severity and remains the best biomarker of soman neurotoxicity.

    View all citing articles on Scopus

    The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army or the Department of Defense. In conducting the research described in this report, the investigators adhered to the ‘Guide for the Care and Use of Laboratory Animals’ (NIH 85-23) of the Institute of Laboratory Animal Resources, National Research Council, U.S.A.

    View full text