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Drug Chem Toxicol, 2015; 38(1): 32–36

! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/01480545.2014.900070

RESEARCH ARTICLE

Acute toxicity of some nerve agents and pesticides in rats

Jan Misik1, Ruzena Pavlikova1, Jiri Cabal1, and Kamil Kuca1,2
1
Faculty of Military Health Sciences, University of Defence, Trebesska, Hradec Kralove, Czech Republic and 2Biomedical Research Center, University
Hospital, Sokolska, Hradec Kralove, Czech Republic

Abstract Keywords
Objectives: Highly toxic organophosphorus compounds (V- and G-nerve agents) were originally Chemical warfare agent, G-agents, military
synthesized for warfare or as agricultural pesticides. Data on their acute toxicity are rare and toxicology, organophosphate, V-agents
patchy. Therefore, there is a need for integrated summary comparing acute toxicity of
organophosphates using different administration routes in the same animal model with the History
same methodology. Based on original data, a summary of in vivo acute toxicity of selected
V- and G-nerve agents (tabun, sarin, soman, VX, Russian VX) and organophosphates paraoxon Received 4 July 2013
(POX) and diisopropyl fluorophosphate (DFP) in rats has been investigated. Materials and Revised 10 February 2014
methods: Male Wistar rats were exposed to organophosphates in several administration routes Accepted 18 February 2014
(i.m., i.p., p.o, s.c., p.c.). The acute toxicity was evaluated by the assessment of median lethal Published online 18 March 2014
dose (LD50, mg kg1) 2, 4, and 24 hours post exposure. Results: V-agents were the most toxic
presented with LD50 ranged from 0.0082 mg kg1 (VX, i.m.) to 1.402 mg kg1 (Russian VX, p.o.),
followed by G-agents (LD50 ¼ 0.069 mg kg1/soman, i.m./ – 117.9 mg kg1/sarin, p.c./), organo-
phosphate POX and DFP (LD50 ¼ 0.321 mg kg1/POX, i.m./ – 420 mg kg1/DFP, p.c./). Generally,
i.m. administration was the most toxic throughout all tested agents and ways of administration
(LD50 ¼ 0.0082 mg kg1/VX/ – 1.399 mg kg1/DFP/) whereas p.c. way was responsible for lowest
acute toxicity (LD50 ¼ 0.085 mg kg1/VX/ – 420 mg kg1/DFP/). Conclusion: The acute toxicity of
selected organophosphorus compounds is summarized throughout this study. Although the
data assessed in rats are rather illustrative prediction for human, it presents a valuable
contribution, indicating the toxic potential and harmfulness of organophosphates.

Introduction dermal absorption (Hamilton et al., 2004; Munro et al., 1994;

Sidell, 1997).
Organophosphates (OP) are esters of phosphorus-containing
OP are generally absorbed through the skin, lungs, eyes,
acids originally developed for warfare or as agricultural
and the gastrointestinal tract. They cause their toxic effects
insecticides. OP were developed before and during World War
mainly by inhibition of acetylcholinesterase (AChE, EC
II but still remain a threat. Even the less toxic organophos-
3.1.1.7), an enzyme which plays an essential role in neuro-
phorus pesticides could be misused by terrorist groups as
transmission (Marrs, 1993; Maxwell et al., 2006). G-agents
cheap and relatively easily available weapons of mass
are able to inhibit AChE more rapidly in comparison with
destruction (Greenfield, 2002; Munro et al., 1994). Among
V-agents. On the other hand, V-agents preferentially react
OP, nerve agents represent the most hazardous compounds
with AChE more than with other plasmatic cholinesterases,
(Figure 1). Nerve agents are historically divided into two
resulting in greater toxicity of V-agents (Munro et al., 1994).
groups – G-agents (German) and V-agents (Venom). G-agents
OP-inhibited AChE is not able to cleave the neurotransmitter
(tabun, sarin, soman etc.) are generally known as relatively
acetylcholine (ACh), resulting in accumulation of ACh in the
volatile agents that particularly cause inhalation toxicity.
synaptic junction and over-stimulation of cholinergic recep-
By contrast, V-agents (VX, Russian VX/VR/, VM, Chinese
tors (Watson et al., 2009). According to the type and
VX, etc.) are more viscous with low volatility, able to persist
localization of receptors, peripheral and central muscarinic
in the environment for a long time. Thus, V-agents are more
and nicotinic symptoms are exhibited. Peripheral muscarinic
potent skin penetrants with the major route of intoxication via
symptoms include lacrimation, salivation, diarrhea, miosis
and bradycardia. Peripheral nicotinic symptoms include
tachycardia, hypertension and local muscle fasciculation
leading to central convulsions and paralysis of skeletal
muscles, including respiratory muscles. Other central symp-
Address for correspondence: Prof. Kamil Kuca, Ph.D., Faculty of toms (both muscarinic and nicotinic) are manifested as
Military Health Sciences, University of Defence, Trebesska 1575, 500 01
Hradec Kralove, Czech Republic. Tel: +420 973 253 028. E-mail: anxiety, confusion, tremor, impaired concentration or respira-
kucakam@pmfhk.cz tory depression (Marrs, 1993). The primary cause of death
DOI: 10.3109/01480545.2014.900070
Figure 1. Chemical structure of OP tabun – (GA), (RS)-ethyl N,N-
dimethylphosphoramidocyanidate; sarin – (GB), (RS)-propan-2-yl
methylphosphonofluoridate; soman – (GD), 3,3-dimethylbutan-2-yl
methylphosphonofluoridate; VX – ethyl ({2-[bis(propan-2-yl)ami-
no]ethyl}sulfanyl)(methyl)phosphinate; VR – N,N-diethyl-2-(methyl-(2-
methylpropoxy)phosphoryl)sulfanylethanamine; POX – diethyl
4-nitrophenyl phosphate; and DFP - bis(propan-2-yl) fluorophosphonate.
in the acute phase of OP poisoning is respiratory failure (Villa
et al., 2007). As well as acute cholinergic manifestations
of OP toxicity, chronic cholinergic and non-cholinergic (non-
specific) symptoms as neurological, locomotive and cognitive
disorders, insomnia, fatigue, headache can occur. These
symptoms usually develop later (days or weeks after an
acute cholinergic crisis) as a consequence of interaction
between OP and other enzymes or neurotransmitters, the
immune system and the metabolism (Abdollahy & Karami-
Mohajery, 2012). Some OP cause a syndrome called
Organophosphate-Induced Delayed Neuropathy (OPIDN)
manifested by chronic neurological and psychological dis-
ability (polyneuropathic disability, motor weakness, paresis,
paralysis, depression etc.).
Besides selected nerve agents, this study investigates the
OP insecticide bis(propan-2-yl) fluorophosphonate (diisopro-
pryl fluorophosphate, DFP) and an active metabolite of the
OP insecticide parathion diethyl 4-nitrophenyl phosphate
(paraoxon, POX) (Figure 1), which act on the same principle
as nerve agents.
Although acute toxicity of OP has been extensively
investigated (Collins et al., 2013; Munro et al., 1994) there
is a lack of comprehensive studies describing this important
toxicological issue. Based on the original data collected
recently at the Department of Toxicology (Faculty of
Military Health Sciences/FMH/), a summary of selected OP
toxicities under various administration routes is presented
in this study. Identical methodology was used throughout
the study in order to deliver a reliable comparison of acute
toxicity in the view of the different toxic agents and routes
of administration.
Nerve agents acute toxicity 33
Material and methods
Chemicals
Nerve agents tabun (GA, ethyl N,N-dimethylphosphor-
amidocyanidate), sarin (GB, propan-2-yl methyl-
phosphonofluoridate), soman (GD, 3,3-dimethylbutan-2-yl
methylphosphonofluoridate), VX (ethyl ({2-[bis(propan-2-
yl)amino]ethyl}sulfanyl)(methyl)phosphinate) and VR
(N,N-diethyl-2-(methyl-(2-methylpropoxy)phosphoryl)sulfa-
nylethanamine) were obtained from Military facility VOP 072
Zemianske Kostolany (Slovak Republic) and were of 95–98%
purity. Purities of agents were established by acidometric
titration. Agent POX (diethyl 4-nitrophenyl phosphate;
90%) and DFP (bis(propan-2-yl) fluorophosphonate;
90%) were obtained from Sigma Aldrich, Ltd. (Czech
Republic) as well as hexane and propylene glycol used for
dilution of OP. Normal saline (0.9% v/w natrium chloride)
was obtained from Noviko Inc. Stock solutions of OP were
made with propylene glycol (1 mg mL1 for nerve agents,
10 mg mL1 for DFP, POX) on the day of the experiment and
were diluted with normal saline immediately before admin-
istration to animals.
Animals
Male Wistar [Crl:(WI)BR] rats (body weight 200–220 g) were
purchased from laboratory animals supply company Velaz
corp. (Czech Republic) and placed at an approved animal
facility at the FMH. The animals were housed in groups of
6 in an environmentally controlled breeding unit (temperature
21 ± 1  C, 12/12 h light/dark cycle) with free access to
standard feed (Cerea corp.) and drinking water. The use of
animals in this study was approved and supervised by the
ethical committee of the FMH. All procedures involving
animals were in accordance with contemporary legislation
of the Czech Republic.
Methods
Experimental animals were randomly divided into five groups
per five to six individuals for each agent and way of
administration. Each group was exposed to five various doses
of the single toxic agent. All substances were applied to non-
anaesthetized animals in standard volume of 1 ml kg1 body
weight via intra-muscular (i.m.), intra-peritoneal (i.p.), sub-
cutaneous (s.c.) or per-oral (p.o.) administration. Undiluted
toxic agents were administered percutaneously (p.c.). With
regard to expected high toxicity of agent VX, small volumes
were necessary for p.c. administration. Thus, agent VX was
administrated as a 0.01% hexane solution. Solutions of OP
were administered i.m. via injection to the muscles of the
right pelvic limb, i.p. via injection to the abdomen, p.o. via
gastric tube into the stomach or s.c. via injection under the
front-dorsal skin of the trunk. Percutaneous administration
was performed as a single line via a pipette onto the clipped
dorsal skin (5  7 cm). Clipping was performed on the day
before the experiment to avoid skin irritation. Percutaneously
treated animals were fixed on plastic platters and placed in a
fume hood during the experiment. Animals treated by i.m.,
s.c., i.p. and p.o. way were kept in breeding boxes after agent
administration. The acute toxicity was evaluated by the
34 J. Misik et al. Drug Chem Toxicol, 2015; 38(1): 32–36

Table 1. Acute toxicity of OP NA and pesticides in male Wistar rats under various ways of administration (i.m., s.c., i.p., p.o, p.c.). 2, 4 and 24 h
median lethal doses (LD50) and confidence limits are shown. There is no time variability if a single data is shown (LD50 ¼ 2hLD50 ¼ 4hLD50 ¼ 24hLD50).
Values of LD50 published previously by other studies are given (ref.) with cross-references stated below. Detailed experimental conditions of referred
studies as strain, sex and age of experimental animals as well as purity of tested compounds and confident limits of LD50 are not included.

LD50 (mg kg1)

Administration TABUN SARIN SOMAN VX VR POX DFP
2h
i.m. 0.183 0.096 0.069 0.0082 0.0153 0.321 1.399
(0.161–0.208) (0.093–0.099) (0.063–0.075) (0.0072–0.0092) (0.0099–0.0239) (0.241–0.387) (1.19–1.50)
24h
0.0141
(0.0116–0.0182)
ref. 0.14,5,6), 0.1017)
s.c. 0.270 0.11 0.12 0.0119 0.0159 0.429 1.58
(0.240–0.310) (0.101–0.120) (0.103–0.139) (0.0084–0.0157) (0.0138–0.0213) (0.35–0.44) (1.255–1.92)
ref. 0.1621), 0.2802) 0.11), 0.1252) 0.07–0.161), 0.1168), 0.0121), 0.0162) 0.4311)
0.112,9,14), 0.0810)
2h 2h
i.p. 0.602 0.51 0.117 0.0456 0.063 1.276 3.20
(0.495–1.239) (0.406–0.638) (0.10–0.126) (0.0363–0.0573) (0.0529–0.0852) (0.812–2.006) (2.19–4.27)
24h 24h
0.565 0.472
(0.434–1.198)
ref. 0.71612) 7.813)
2h
p.o. 3.6 0.67 0.37 0.189 1.402 (1.0–1.58) 2.519 3.331
(2.69–4.82) (0.59–0.77) (0.30–0.44) (0.169–0.213) (2.203–2.881) (3.00–3.80)
24h
0.122
(0.112–0.134)
ref. 1.063) 0.13)
4h 4h 4h 4h
p.c. 83.0 117.9 9.987 40.150 40.50 450  420
24h 24h 24h 24h
(53.97–117.0) (89.39–155.6) (7.165–13.91) 0.0849 0.392 4.373 300.0
(0.079–0.10) (0.327–0.466) (1.588–8.843) (203.6–429.0)
ref. 181), 12.63) 2.5 1,3)
0.13)

References for Table 1: 1) John et al. 2009 2) Shih & McDonough 1999 3) Munro et al. 1994 4) Damodaran et al. 2003 5) Jones et al. 2000 6) Khan et al.
2000 7) Abdel-Rahman et al. 2002 8) Maxwell et al. 1987 9) Shih 1990 10) Myhrer et al. 2005 11) Villa et al. 2007 12) Mehrani et al. 2008 13) Nieminen
et al. 1991 14) Langston et al. 2012

assessment of median lethal dose (LD50, mg kg1) and

confidence limit which was calculated by probit analysis
of deaths occurring within 2, 4 and 24 h respectively.
LD50 values were assessed 4 and 24 h in the groups of
p.c. administered V-agents and pesticides with regard to
slow action of these agents. Exposed animals that survived
24 h were euthanized in 100% CO2 atmosphere.

Results
The summary of acute toxicity of nerve agents and pesticides
expressed as LD50 is shown in Table 1. Rats intoxicated with
OP showed typical signs of intoxication followed by recovery
or death, depending on the kind of agent, the dose applied and
the route of administration. Cholinergic signs were observed
in G-agent groups at first, followed by V-agents and
pesticides. Local fasciculation of muscles usually occurred
as the first sign. In i.m. treated groups, local fasciculation Figure 2. Shift of OP acute toxicity (24hLD50) in relation to way of
administration. Ways of administration are sentenced in descending
usually started several min (2.5–3.5 min, soman; 7.5–9.5 min, order according to expected toxic effect.
VX) post-exposure. Local fasciculation expanded gradually
according to the applied dose and the route of administration,
leading to strong central convulsions that ended in respiratory The LD50 varied from 0.0082 mg kg1 (VX, i.m.) to
crisis (apnoea) and death when the lethal dose was applied. 300 mg kg1 (DFP, p.c.). V-agents (VX, VR) were the most
Ataxia, mastication, salivation, miosis, and piloerection were toxic in all types of administration, followed by G-agents.
also observed throughout all treated groups. Agent DFP was the less toxic in comparison with other tested
The acute toxicity was assessed at 3 time points -2, 4 and OP, except p.o. administration which was more toxic than
24 h post-exposure. Deaths usually occurred within first two h administration of nerve agent tabun via the same way (3.3
and the LD50 remained identical till 24 h post-exposure. There versus 3.6 mg kg1). In general, rats were most sensitive to
was a time difference between 2 h and 24 h LD50 in i.p. i.m. administration related to better system availability in
administered G-agents tabun and sarin and V-agents VX and comparison with other ways of administration (Figure 2). As
VR under p.o. and i.m. administration, respectively (Table 1). expected, the toxicity decreased dependent on the route
DOI: 10.3109/01480545.2014.900070
of administration – i.m.4s.c.4i.p.4p.o.4p.c. – except
V-agents (p.c.4p.o.). Based on different routes of adminis-
tration, the less physiological sensitivity was found in
POX whereas sarin was the most sensitive. The difference
between the most (i.m.) and the least (p.c.) sensitive
route of administration varied more than a thousand times
in sarin-treated groups (Figure 2).
Discussion
As anticipated, the route of administration was demonstrated
as an important factor causing substantial differences in
individual OP toxicity. Generally, i.m. administration was the
most toxic in all cases, resulting from avoidance of the
intestinal tract and thus first pass metabolism in the liver
(Karalliede et al., 2003). Even so, oral and especially dermal
exposition led to the highest values of LD50. The upper skin
surface consisting of a hydrophobic layer of cornified
epidermocytes (stratum corneum), represents a principal
barrier preventing permeation of xenobiotics (Elias, 1983).
Lipophilic OP overcome the stratum corneum gradually and
tend to form depots in the subcutaneous adipose tissue. OP
could be subsequently released from such depots to the
systemic circulation, thus inducing a delayed toxic effect
(Bjarnason et al., 2008; Chilcott et al., 2005). In the case of
oral administration, OP are destroyed (hydrolyzed) in the
gastric acid environment, and moreover the gastrointestinal
tract acts also as a natural barrier. Thus, higher lethal doses
were recorded via p.c. and p.o. administration.
Acute toxicity of OP descended in the order V-agents4
G-agents4pesticides. Variable toxico-kinetics and toxico-
dynamics of particular OP depends mainly on different
AChE-inhibiting potencies, aging rates and lipophilia (Joosen,
2009; Marrs, 1993). High lipophlilia is usually presented by
efficacious bio-distribution and easier penetration through the
biological barriers such as skin or blood-brain barrier. In this
study, highly lipophilic VX (logKow ¼ 2.09) was the most
toxic agent represented by the values of 24hLD50 within the
range of 0.008–0.122 mg kg1 via all tested administration
routes. The data obtained here match formerly reported VX
toxicity (Table 1). Agent VR, a structural isomer of VX, was
the second most toxic compound among tested substances and
routes of administration, except p.o. route (Figure 2). Extreme
toxicity of V-agents is also caused by preferential reaction
with AChE, contrary to G-agents which are more prone to be
hydrolyzed by other cholinesterases (Munro et al., 1994).
Although VX was the most potent OP, manifestation of
cholinergic signs occurred relatively late, even several h post-
exposure (p.c.). This is most likely due to a slow tissue
penetration rate and tendency of VX to form depots. Delayed
systemic distribution with maximal plasma levels several h
after VX administration is typical (Van der Schans et al.,
2003). In this study, V-agents exhibited strong affinity to
skin and their dermal toxicity was even higher than oral
toxicity, as has been previously reported for some OP
pesticides (Karalliede et al., 2003). The difference was
distinctive in VR where dermal toxicity was more than
three times higher than oral toxicity.
Although G-agents were less toxic in comparison to
V-agents, manifestation of toxic signs was usually more rapid
Nerve agents acute toxicity 35
especially in the most potent G-agent soman. When lethal
doses of soman were applied, rapid manifestation of AChE
inhibition occurred in several minutes (fasciculation, central
convulsions) followed by respiratory crisis and death.
Velocity of soman-induced signs can be explained by the
high lipophilia of soman (logKow ¼ 1.824; Czerwinski et al.,
1998) and therefore easy passage of soman through the blood-
brain barrier, followed by a strong central effect (Joosen
2009). Moreover, spontaneous (or therapeutic) reactivation
of soman is limited due to rapid aging of inhibited AChE
(Kassa, 2002; Talbot et al., 1988). All these characteristics
contribute to a rapid progression of soman poisoning.
Majority of symptoms occurred in first few h after soman
administration and survival of this period was accompanied
by successive reduction of cholinergic signs. Therefore,
survival to 24 h after survival to 2 h was due to the relative
absence of further symptoms or their lowered intensity in the
intervening period. This may help explain the fact that
all LD50 was consistent across all time points and routes
of administration in soman poisoning. A similar effect was
found in the rest of G-agents, except for a mild time difference
between i.p. LD50 (Table 1).
G-agents had a lower tendency to permeate through the
skin due to high volatility. Accordingly, the difference
between i.m. and dermal toxicity was substantial, varying
more than a thousand times. Obtained toxicities of G-agents
were in accordance with published data for s.c. administration
of soman, tabun and sarin (Table 1), whereas p.c. adminis-
tered tabun and soman were substantially less toxic in the
present study (83 versus 18 mg kg1 in tabun, 117.9 versus
2.5 mg kg1 in sarin, Table 1). Nevertheless, the major route
of exposure to volatile G-agents in real conditions is expected
to be through inhalation (Greenfield et al., 2002; Shih &
McDonough, 1999) which was not used in this study. Vapors
and aerosols, the most common form of G-agents, cause local
effects to the eyes and respiratory system within seconds
(Sidell, 1997). Median lethal concentration (LCt50, mg min1
m3) in rats was found to be 450 and 220 mg min1 m3 for
tabun and sarin, respectively (Sidell, 1997). Collins et al.
(2013) found inhalational LD50 for G-agents sarin and soman
to be 0.167 and 0.154 mg kg1, respectively.
POX and DFP were in general less potent than nerve
agents. Their effect was rather slow, similar to that of
V-agents, manifested with cholinergic signs starting in tens
of minutes or h after administration. On the other hand,
lipophilic and low-volatile POX was proved to be a slow
but potent skin-permeant characterized by dermal toxicity
even higher than the toxicity of the most potent G-agent
soman. Also the oral toxicity of both pesticides was higher
than the oral toxicity of the less potent G-agent tabun.
In comparison with published data, an identical LD50
for s.c. administered POX was achieved in a study of Villa
et al. (2007).
A summary of selected OP acute toxicity exposure was
investigated in rats. Despite there is a multifactorial influence
on experimental assessment of OP toxicity as a potential
source of inter-laboratory variability (Karalliede et al., 2003),
good agreement with published data was achieved throughout
this study. Substantial difference was found in dermally-
administered G-agents, tabun and sarin, which were several
36 J. Misik et al.
times less potent than has been published before (John et al.,
2009; Munro et al., 1994). The cause of this difference is
unclear however, different physicochemical characteristics of
the agents such as purity or dilution in organic solvent, as well
as the method of dermal exposure and individual character-
istics of experimental animals (strain, gender, age, etc.) might
be considered. Especially dilution in organic solvents such as
polyethylene glycol or dimethyl sulfoxide prior to dermal
exposure can elevate acute toxicity by enhancing permeation
(Sinha & Maninder, 2000).
According to the ranking system of the European
Commission Directive (67/548/EEC) all of the tested OP
could be categorized as very toxic with oral
LD50525 mg kg1 (R 28). There is a persistent failure to
predict the toxicity for humans from animal data due to the
lack of correlation between laboratory findings and clinical
experience (Karalliede et al., 2003), but animal data are a
valuable contribution indicating the toxic potential and
harmfulness of OP and the need for adequate countermeasures
against chemical weapons and pesticides.
Acknowledgements
The authors wish to acknowledge Mrs. Eva Vodakova for her
skillful technical assistance and Dr. Ann Pocknell for
providing language help.
Declaration of interest
This work was financially supported by the long-term
organization development plan 1011 and development plans
of University hospital Hradec Kralove. The funders had no
role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
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