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Archives of Toxicology

, Volume 92, Issue 2, pp 873–892 | Cite as

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

  • E. Bloch-ShildermanEmail author
  • I. Rabinovitz
  • I. Egoz
  • G. Yacov
  • N. Allon
  • U. Nili
Organ Toxicity and Mechanisms

Abstract

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.

Keywords

Continuous VX exposure Low dose Cholinesterase (ChE) Alzet pumps Organophosphorous Radiotelemetric ECoG recordings Circadian rhythm Forelimbs motor skills TSPO M2 receptors 

Abbreviations

ACh

Acetylcholine

AChE

Acetylcholinesterase

AEL

Airborne exposure limits

EEG

Electroencephalogram

ECoG

Electrocorticogram

FFT

Fast Fourier transform

OP

Organophosphate

OPNA

Organophosphorus nerve agents

TSPO

Translocator protein

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

Supplementary material

204_2017_2108_MOESM1_ESM.docx (74 kb)
Circadian rhythm of body temperature and motor activity during continuous exposure to 2.25 or 13.5 µg/kg/day of VX. Following baseline recordings, rats were continuously exposed to propylene glycol (Sham) or VX (2.25 (a,b) or 13.5 µg/kg/day (c,d)) via subcutaneously implanted mini osmotic pumps for 4 weeks (n=4/group in both experiments). Recordings from the 7 days pre and 15 days post beginning of exposure are shown. Telemetry data collected every 5 minutes was analyzed and presented using four hour bins. Each data point represents the mean ± SEM of the group’s delta in body temperature (a,c) and motor activity (b,d) relative to the average of these measures along the entire duration of the experiment presented (Black dotted line depicting a delta of zero. For more details regarding the analysis see materials and methods). In all graphs the black arrow denotes beginning of exposure. In two separate additional experiments with both VX doses as compared to Sham (n=4 per group in each experiment) a similar result was obtained (data not shown) (DOCX 73 kb)

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • E. Bloch-Shilderman
    • 1
    Email author
  • I. Rabinovitz
    • 1
  • I. Egoz
    • 1
  • G. Yacov
    • 1
  • N. Allon
    • 1
  • U. Nili
    • 1
  1. 1.Department of PharmacologyIsrael Institute for Biological ResearchNess ZionaIsrael

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