Skip to main content

Advertisement

SpringerLink
Log in

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

  • Organ Toxicity and Mechanisms
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

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

References

  • Abou-Donia MB, Goldstein LB, Bullman S, Tu T, Khan WA, Dechkovskaia AM, Abdel-Rahman AA (2008) Imidacloprid induces neurobehavioral deficits and increases expression of glial fibrillary acidic protein in the motor cortex and hippocampus in offspring rats following in utero exposure. J Toxicol Environ Health A 71:119–123

    Article  CAS  PubMed  Google Scholar 

  • Allon N, Chapman S, Egoz I, Rabinovitz I, Kapon J, Weissman BA, Yacov G, Bloch-Shilderman E, Grauer E (2011) Deterioration in brain and heart functions following a single sub-lethal (0.8 LCt50) inhalation exposure of rats to sarin vapor: a putative mechanism of the long term toxicity. Toxicol Appl Pharmacol 253:31–37

    Article  CAS  PubMed  Google Scholar 

  • Ashani Y, Pistiner S (2004) Estimation of the upper limit of human butyrylcholinesterase dose required for protection against organophosphates toxicity: a mathematically based toxokinetic model. Toxicol Sci 77:358–367

    Article  CAS  PubMed  Google Scholar 

  • Atchison CR, Sheridan RE, Duniho SM, Shih TM (2004) Development of a guinea pig model for low-dose, long-term exposure to organophosphorus nerve agents. Toxicol Mech Meth 14:183–194

    Article  CAS  Google Scholar 

  • Benavides J, Dubois A, Scatton B (1999) Peripheral type benzodiazepine binding sites as a tool for the detection and quantification of CNS injury. Curr Prot Neurosci 16:1–7

    Google Scholar 

  • Bennion BJ, Lau EY, Fattebert JL, Huang P, Schwegler P, Corning W, Lightstone FC (2013) Modeling the binding of CWAs to AChE and BuChE. Mil Med Sci Lett 82:102–114

    Google Scholar 

  • Benton BJ, McGuire JM, Sommerville DR, Dabisch PA, Jakubowski EM, Matson KL, Mioduszewski RJ, Thomson SA (2006) Effects of whole-body VX vapor exposure on lethality in rats. Inhal Toxicol 18:1091–1099

    Article  CAS  PubMed  Google Scholar 

  • Black RM, Harrison JM (1996) The chemistry of organophosphorus chemical warfare agents. In: Hartley FR (ed) The chemistry of organophosphorus compounds, vol 4. Wiley, Chichester, pp 783–798

    Chapter  Google Scholar 

  • Bloch-Shilderman E, Kadar T, Levy A, Sahar R, Rabinovitz I, Gilat E (2005) Subcellular alterations of protein kinase C isozymes in the rat brain after organophosphate poisoning. J Pharmacol Exp Ther 313:1–8

    Article  Google Scholar 

  • Bloch-Shilderman E, Rabinovitz I, Egoz I, Raveh L, Allon N, Grauer E, Gilat E, Weissman BA (2008) Chronic exposure of rats to low doses of the nerve-agent VX: physiological, behavioral, histopathological and neurochemical studies. Toxicol Appl Pharmacol 231:17–23

    Article  CAS  PubMed  Google Scholar 

  • Bomser JA, Casida JE (2001) Diethylphosphorylation of rat cardiac M2 muscarinic receptor by chlorpyrifos oxon in vitro. Toxicol Lett 119:21–26

    Article  CAS  PubMed  Google Scholar 

  • Bosković B (1979) The influence of 2-/o-cresyl/-4 H-1:3:2-benzodioxa-phosphorin-2-oxide (CBDP) on organophosphate poisoning and its therapy. Arch Toxicol 42:207–216

    Article  PubMed  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  • Brown MA, Brix KA (1998) Review of health consequences from high-, intermediate-, and low-level exposure of organophosphate nerve agents. J Appl Toxicol 18:393–408

    Article  CAS  PubMed  Google Scholar 

  • Bueters TJH, Joosen MJA, Van Helden HPM, Ijzerman AP, Danhof M (2003) Adenosine A1 receptor agonist N6-cyclopentyladenosine affects the inactivation of acetylcholinesterase in blood and brain by sarin. J Pharmacol Exp Ther 304:1307–1313

    Article  CAS  PubMed  Google Scholar 

  • Burchfiel JL, Duffy FH (1982) Organophosphate neurotoxicity: chronic Effects of sarin on the electroencephalogram of monkey and man. Neurobehav Toxicol Teratol 4:767–778

    CAS  PubMed  Google Scholar 

  • Cape EG, Manns ID, Alonso A, Beaudet A, Jones BE (2000) Neurotensin-induced bursting of cholinergic basal forebrain neurons promotes γ and θ cortical activity together with waking and paradoxical sleep. J Neurosci 20:8452–8461

    CAS  PubMed  Google Scholar 

  • Churchill L, Pazdernik TL, Jackson JL, Nelson SR, Samson FE, McDonough JH Jr, McLeod CG Jr (1985) Soman-induced brain lesions demonstrated by muscarinic receptor autoradiography. Neurotoxicology 6:81–90

    CAS  PubMed  Google Scholar 

  • Collombet JM (2011) Nerve agent intoxication: recent neuropathophysiological findings and subsequent impact on medical management prospects. Toxicol Appl Pharmacol 255:229–241

    Article  CAS  PubMed  Google Scholar 

  • Columbus I, Waysbort D, Marcovitch I, Yehezkel L, Mizrahi DM (2012) VX fate on common matrices: evaporation versus degradation. Environ Sci Technol 46:3921–3927

    Article  CAS  PubMed  Google Scholar 

  • Duffy FH, Burchfiel JL, Bartels PH, Gaon M, Sim VM (1979) Long-term effects of an organophosphate upon the human electroencephalogram. Toxicol Appl Pharmacol 47:161–176

    Article  CAS  PubMed  Google Scholar 

  • Ellin R (1982) Anomalies in theories and therapy of intoxication by potent organophosphorus anticholinesterase compounds. Gen Pharmacol 13:457–466

    Article  CAS  PubMed  Google Scholar 

  • Ellman GL, Courtney KD, Andres V, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95

    Article  CAS  PubMed  Google Scholar 

  • Federal Register (2003) Final recommendations for protecting human health from potential adverse effects of exposure to agents GA, GB, and VX. Fed Reg 68(196):58348–58351

    Google Scholar 

  • Fonnum F, Sterri SH (1981) Factors modifying the toxicity of organophosphorous compounds including soman and sarin. Fundam Appl Toxicol 1(2):143–147

    Article  CAS  PubMed  Google Scholar 

  • Genovese RF, Benton BJ, Lee EH, Shippee SJ, Jakubowski EM (2007) Behavioral and biochemical evaluation of sub-lethal inhalation exposure to VX in rats. Toxicology 232:109–118

    Article  CAS  PubMed  Google Scholar 

  • Gordon CJ, Padnos BK (2002) Dietary exposure to chlorpyrifos alters core temperature in the rat. Toxicology 177:215–226

    Article  CAS  PubMed  Google Scholar 

  • Graziani S, Christin D, Daulon S, Breton P, Perrier N, Taysse L (2014) Effects of repeated low-dose exposure of the nerve agent VX on monoamine levels in different brain structures in mice. Neurochem Res 39:911–921

    Article  CAS  PubMed  Google Scholar 

  • Gundavarapu S, Zhuang J, Barrett EG, Xu F, Russell RG, Sopori ML (2014) A critical role of acute bronchoconstriction in the mortality associated with high-dose sarin inhalation: effects of epinephrine oxygen therapies. Toxicol Appl Pharmacol 274:200–208

    Article  CAS  PubMed  Google Scholar 

  • Gura S, Tzanani N, Herschkovitz M, Barak R, Dagan S (2006) Fate of chemical warfare agent VX in asphalt: a novel approach for quantitation of VX in organic surfaces. Arch Environ Contam Toxicol 51:1–10

    Article  CAS  PubMed  Google Scholar 

  • Hulet SW, Sommerville DR, Miller DB, Scotto JA, Muse WT, Burnett DC (2014) Comparison of sarin and cyclosarin toxicity by subcutaneous, intravenous and inhalation exposure in Gottingen minipigs. Inhal Toxicol 26:175–184

    Article  CAS  PubMed  Google Scholar 

  • Jamal GA (1997) Neurological syndromes of organophosphorous compounds. Adverse Drug React Toxicol Rev 16:133–170

    CAS  PubMed  Google Scholar 

  • Jamal GA, Hansen S, Julu PO (2002) Low level exposures to organophosphorus esters may cause neurotoxicity. Toxicology 181–182:23–33

    Article  PubMed  Google Scholar 

  • Jimmerson VR, Shih TM, Mailman RB (1989) Variability in soman toxicity in the rat: correlation with biochemical and behavioral measures. Toxicology 57:241–254

    Article  CAS  PubMed  Google Scholar 

  • Johnson CD, Russell RL (1975) A rapid simple radiometric assay for cholinesterase suitable for multiple determinations. Anal Biochem 64:229–238

    Article  CAS  PubMed  Google Scholar 

  • Jokanovic M (2009) Current understanding of the mechanism involved in metabolic detoxification of warfare nerve agents. Toxicol Lett 188:1–10

    Article  CAS  PubMed  Google Scholar 

  • Kamel F, Hoppin JA (2004) Association of pesticide exposure with neurologic dysfunction and disease. Environ Health Perspect 112:950–958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kassa J, Kunesova G (2006) The influence of antidotal treatment of low-level tabun exposure on cognitive functions in rats using a water maze. Neurotox Res 9:39–45

    Article  CAS  PubMed  Google Scholar 

  • Kassa J, Pecka M, Tichy M, Bajgar J, Koupilova M, Herink J, Krocova Z (2001) Toxic effects of sarin in rats at 3 months following single or repeated low-level inhalation exposure. Pharmacol Toxicol 88:209–212

    Article  CAS  PubMed  Google Scholar 

  • Kryger M, Monjan A, Bliwise D, Ancoli-Israel S (2004) Sleep, health, and aging. Bridging the gap between science and clinical practice. Geriatrics 59(24–26):29–30

    Google Scholar 

  • Lee MG, Manns ID, Alonso A, Jones BE (2004) Sleep-wake related discharge properties of basal forebrain neurons recorded with micropipettes in head-fixed rats. J Neurophysiol 92:1182–1198

    Article  PubMed  Google Scholar 

  • Lee MG, Hassani OK, Alonso A, Jones BE (2005) Cholinergic basal forebrain neurons burst with theta during waking and paradoxical sleep. J Neurosci 25:4365–4369

    Article  CAS  PubMed  Google Scholar 

  • Lenz DE, Maxwell DM, Austin LW (1997) Development of a rat model for subacute exposure to the toxic organophosphate VX. J Am Coll Toxicol 15:s69–s77

    Article  Google Scholar 

  • Macilwain C (1993) Study proves Iraq used nerve gas. Nature 363:3

    Article  CAS  PubMed  Google Scholar 

  • Marrs TC (2007) Toxicology of organophosphate nerve agents. In: Marrs TC, Maynard RL, Sidell F (eds) Chemical warfare agents: toxicology and treatment, 2nd edn. Wiley, Chichester, pp 191–222

    Chapter  Google Scholar 

  • Meeter E, Wolthuis OL (1968) The spontaneous recovery of respiration and neuromuscular transmission in the rat after anticholinesterase poisoning. Eur J Pharmacol 2:377–386

    Article  CAS  PubMed  Google Scholar 

  • Metcalf DR, Holmes JH (1969) EEG, psychological and neurological alterations in humans with organophosphate exposure. Ann NY Acad Sci 160:357–365

    Article  CAS  PubMed  Google Scholar 

  • Miller JH, Gibson VA, McKinney M (1991) Binding of [3H]AF-DX 384 to cloned and native muscarinic receptors. J Pharmacol Exp Ther 259:601–607

    CAS  PubMed  Google Scholar 

  • Moore DH (1998) Health effects of exposure to low doses of nerve agents—a review of present knowledge. Drug Chem Toxicol 21:123–130

    Article  CAS  PubMed  Google Scholar 

  • Munro NB, Ambrose KR, Watson AP (1994) Toxicity of the organophosphate chemical warfare agents GA, GB, and VX: implications for public protection. Environ Health Perspect 102:18–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Munro NB, Talmage SS, Griffin GD, Waters LC, Watson AP, King JF, Hauschild V (1999) The sources, fate, and toxicity of chemical warfare agent degradation products. Environ Health Perspect 107:933–974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muse WT, Thomson S, Crouse C, Matson K (2006) Generation, sampling, and analysis for low-level GB (Sarin) and GF (Cyclosarin) vapor for inhalation toxicology studies. Inhal Toxicol 18:1101–1108

    Article  CAS  PubMed  Google Scholar 

  • Nagao M, Takatori T, Matsuda Y, Nakajima M, Iwase H, Iwadate K (1997) Definitive evidence for the acute sarin poisoning diagnosis in the Tokyo subway. Toxicol Appl Pharmacol 144:198–203

    Article  CAS  PubMed  Google Scholar 

  • Naik RS, Liu W, Saxena A (2013) Development and validation of a simple assay for the determination of cholinesterase activity in whole blood of laboratory animals. J Appl Toxicol 33:290–300

    Article  PubMed  Google Scholar 

  • National Research Council (2005) Impact of revised airborne exposure limits on non-stockpile chemical materiel program activities. The National Academic Press, Washington DC

    Google Scholar 

  • Nishiwaki Y, Maekawa K, Ogawa Y, Asukai N, Minami M, Omae K, Sarin Health Effects Study Group (2001) Effects of sarin on the nervous system in rescue team staff members and police officers 3 years after the Tokyo subway sarin attack. Environ Health Perspect 109:1169–1173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oswal DP, Garrett TL, Morris M, Lucot JB (2013) Low-dose sarin exposure produces long term changes in brain neurochemistry of mice. Neurochem Res 38:108–116

    Article  CAS  PubMed  Google Scholar 

  • Pearce PC, Crofts HS, Muggleton NG, Ridout D, Scott EAM (1999) The effects of acutely administered low dose sarin on cognitive behaviour and the electroencephalogram in the common marmoset. J Psychopharmacol 13:128–135

    Article  CAS  PubMed  Google Scholar 

  • Peng X, Perkins MW, Simons J, Witriol AM, Rodriguez AM, Benjamin BM, Devorak J, Sciuto AM (2014) Acute pulmonary toxicity following inhalation exposure to aerosolized VX in anesthetized rats. Inhal Toxicol 26:371–379

    Article  CAS  PubMed  Google Scholar 

  • Pizarro JM, Chang WE, Bah MJ, Wright LKM, Saviolakis GA, Alagappan A, Robison CL, Shah JD, Meyerhoff JL, Cerasoli DM, Midboe EG, Lumley LA (2012) Repeated exposure to sublethal doses of the organophosphorus compound VX activates BDNF expression in mouse brain. Toxicol Sci 126:497–505

    Article  CAS  PubMed  Google Scholar 

  • Raber E, Carlsen T, Folks K, Kirvel R, Daniels J, Bogen K (2004) How clean is clean enough? Recent developments in response to threats posed by chemical and biological warfare agents. Int J Environ Health Res 14:31–41

    Article  CAS  PubMed  Google Scholar 

  • Ray DE (1998) Chronic effects of low level exposure to anticholinesterases—a mechanistic review. Toxicol Lett 102–103:527–533

    Article  PubMed  Google Scholar 

  • Reiter G, Müller S, Hill I, Weatherby K, Thiermann H, Worek F, Mikler J (2015) In vitro and in vivo toxicological studies of V nerve agents: molecular and stereoselective aspects. Toxicol Lett 232:438–448

    Article  CAS  PubMed  Google Scholar 

  • Rocksen D, Elfsmark D, Heldestad V, Wallgren K, Cassel G, Nyberg G (2008) An animal model to study health effects during continuous low-dose exposure to the nerve agent VX. Toxicology 250:32–38

    Article  CAS  PubMed  Google Scholar 

  • Romano JA Jr, McDonough JH, Sheridan R, Sidell FR (2001) Health effects of low-level exposure to nerve agents. In: Somani SM, Romano JA Jr (eds) Chemical warfare agents: toxicity at low levels, 1st edn. CRC Press, Taylor & Francis Group, Boca Raton, pp 1–24

    Google Scholar 

  • Salvi RM, Lara DR, Ghisolfi ES, Portela LV, Dias RD, Souza DO (2003) Neuropsychiatric evaluation in subjects chronically exposed to organophosphate pesticides. Toxicol Sci 72:267–271

    Article  CAS  PubMed  Google Scholar 

  • Shih TM, Hulet SW, McDonough JH (2006) The effects of repeated low-dose sarin exposure. Toxicol Appl Pharmacol 215:119–134

    Article  CAS  PubMed  Google Scholar 

  • Sidell RF, Groff WA (1974) The reactivatibility of cholinesterase inhibited by VX and sarin in man. Toxicol Appl Pharmacol 27:241–252

    Article  CAS  PubMed  Google Scholar 

  • Signorino M, Pucci E, Brizioli E, Cacchio G, Nolfe G, Angeleri F (1996) EEG power spectrum typical of vascular dementia in a subgroup of Alzheimer patients. Arch Gerontol Geriatr 23:139–151

    Article  CAS  PubMed  Google Scholar 

  • Sweeny RE, Maxwell DM (2003) A theoretical expression for the protection associated with stoichiometric and catalytic scavengers in a single compartment model of organophosphorus poisoning. Math Biosci 181:133–143

    Article  Google Scholar 

  • Terry AV Jr (2012) Functional consequences of repeated organophosphate exposure: potential non-cholinergic mechanisms. Pharmacol Ther 134:355–365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tillman GD, Calley CS, Green TA, Buhl VI, Biggs MM, Spence JS, Briggs RW, Haley RW, Hart J, Kraut MA Jr (2012) Event-related potential patterns associated with hyperarousal in Gulf War illness syndrome groups. Neurotoxicology 33:1096–1105

    Article  PubMed  PubMed Central  Google Scholar 

  • Timofeeva OA, Gordon CJ (2001) Changes in EEG power spectra and behavioral states in rats exposed to the acetylcholinesterase inhibitor chlorpyrifos and muscarinic agonist oxotremorine. Brain Res 893:165–177

    Article  CAS  PubMed  Google Scholar 

  • Timofeeva OA, Gordon CJ (2002) EEG spectra, behavioral states and motor activity in rats exposed to the acetylcholinesterase inhibitor chlorpyrifos. Pharmacol Biochem Behav 72:669–679

    Article  CAS  PubMed  Google Scholar 

  • Tonduli LS, Testylier G, Pernot Marino I, Lallement G (1999) Triggering of soman-induced seizures in rats: multiparametric analysis with special correlation between enzymatic, neurochemical and electrophysiological data. J Neurosci Res 58:464–473

    Article  CAS  PubMed  Google Scholar 

  • van der Schans MJ, Lander BJ, van der Wiel H, Langenberg JP, Benschop HP (2003) Toxicokinetics of the nerve agent (±)-VX in anesthetized and atropinized hairless guinea pigs and marmosets after intravenous and percutaneous administration. Toxicol Appl Pharmacol 191:48–62

    Article  PubMed  Google Scholar 

  • van Helden HPM, Vanwersch RAP, Kuijpers WC, Trap HC, Philippens IHC, Benschop HP (2004) Low levels of sarin affect the EEG in marmoset monkeys: a pilot study. J Appl Toxicol 24:475–483

    Article  PubMed  Google Scholar 

  • Watson AP, Jones TD, Adams JD (1992) Relative potency estimates of acceptable residues and reentry intervals after nerve agent release. Ecotoxicol Environ Saf 23:328–342

    Article  CAS  PubMed  Google Scholar 

  • Watson AP, Opresko D, Young R, Hauschild V (2006) Development and application of acute exposure guideline levels (AEGLs) for chemical warfare nerve and sulfur mustard agents. J Toxicol Environ Health B Crit Rev 9:173–263

    Article  CAS  PubMed  Google Scholar 

  • Weissman BA, Raveh L (2003) Peripheral benzodiazepine receptors: on mice and human brain imaging. J Neurochem 84:432–437

    Article  CAS  PubMed  Google Scholar 

  • Whishaw IQ, Coles BL (1996) Varieties of paw and digit movement during spontaneous food handling in rats: postures, bimanual coordination, preferences, and the effect of forelimb cortex lesions. Behav Brain Res 77:135–148

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Israel Institute for Biological Research, P.O. Box 19, 74100, Ness Ziona, Israel

    E. Bloch-Shilderman, I. Rabinovitz, I. Egoz, G. Yacov, N. Allon & U. Nili

Authors
  1. E. Bloch-Shilderman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I. Rabinovitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. Egoz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Yacov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N. Allon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. U. Nili
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. Bloch-Shilderman.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

204_2017_2108_MOESM1_ESM.docx

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)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bloch-Shilderman, E., Rabinovitz, I., Egoz, I. et al. Determining a threshold sub-acute dose leading to minimal physiological alterations following prolonged exposure to the nerve agent VX in rats. Arch Toxicol 92, 873–892 (2018). https://doi.org/10.1007/s00204-017-2108-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-017-2108-5

Keywords

Search

Navigation