Determining a threshold sub-acute dose leading to minimal physiological alterations following prolonged exposure to the nerve agent VX in rats

VX, a potent inhibitor of cholinesterase (ChE), is considered as one of the most toxic, persistent and least volatile nerve agents. VX is absorbed in various environmental surfaces and is gradually released long after its initial dispersal. Its toxicity is mainly caused by disrupting central and per...

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Bibliographic Details
Published in:Archives of toxicology 2018-02, Vol.92 (2), p.873-892
Main Authors: Bloch-Shilderman, E., Rabinovitz, I., Egoz, I., Yacov, G., Allon, N., Nili, U.
Format: Article
Language:English
Subjects:
Animals
Biological & chemical weapons
Biomarkers - blood
Biomedical and Life Sciences
Biomedicine
Body Temperature
Body Weight
Brain
Brain - drug effects
Brain damage
Brain injury
Carrier Proteins - metabolism
Chemical Warfare Agents - toxicity
Cholinergic nerves
Cholinesterase
Cholinesterase Inhibitors - toxicity
Cholinesterases - blood
Cholinesterases - metabolism
Circadian rhythms
Dispersal
Dose-Response Relationship, Drug
Environmental Health
Exposure
Intoxication
Male
Motor Activity
Muscles
Muscles - drug effects
Nerve agents
Nerve Agents - toxicity
Nervous system
Occupational Medicine/Industrial Medicine
Organ Toxicity and Mechanisms
Organothiophosphorus Compounds - toxicity
Pharmacology/Toxicology
Physiological effects
Physiology
Rats
Rats, Sprague-Dawley
Receptor density
Receptor, Muscarinic M2 - metabolism
Receptors, GABA-A - metabolism
Reduction
Toxicity
Toxicity Tests, Chronic
Wave dispersion
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Summary:VX, a potent inhibitor of cholinesterase (ChE), is considered as one of the most toxic, persistent and least volatile nerve agents. VX is absorbed in various environmental surfaces and is gradually released long after its initial dispersal. Its toxicity is mainly caused by disrupting central and peripheral cholinergic nervous system activity, leading to potential long-term detrimental effects on health. The primary objective of the present study was to assess the threshold VX dose leading to minimal physiological alterations following prolonged VX exposure. Characterization of such a threshold is crucial for dealing with unresolved operative dilemmas such as when it is safe enough to resettle a population that has been evacuated from a VX-contaminated area. Rats, continuously exposed to various doses of VX (0.225–45 µg/kg/day) for 4 weeks via implanted mini-osmotic pumps, showed a dose-dependent and continuous decrease in ChE activity in whole blood, brain and muscles, ranging between 20 and 100%. Exposure to 13.5 µg/kg/day led to a stable low ChE activity level (~ 20%), accompanied by transient and negligible electrocorticogram spectral power transformations, especially in the theta and alpha brain wave frequencies, and a significant decrease in total brain M2 receptor density. These changes were neither accompanied by observable signs of intoxication nor by changes in motor function, circadian rhythm or TSPO level (a reliable marker of brain damage). Following exposure to lower doses of 2.25 and 0.225 µg/kg/day, the only change measured was a reduction in ChE activity of 60 and 20%, respectively. Based on these results, we delineate ChE inhibition as the physiological measure most susceptible to alterations following prolonged VX exposure, and determine for the first time the threshold sub-acute VX dose for minimal physiological effects (up to 20% reduction in ChE activity) in the rat as 0.225 µg/kg/day.
ISSN:0340-5761
1432-0738
DOI:10.1007/s00204-017-2108-5