Page 116 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Chemicals of Terrorism Chapter | 5 83

VetBooks.ir the “G” agents (Sidell et al., 1997). “V” agents, such as and excreted by the kidneys (Little et al., 1986). Mouse
studies reveal that approximately 50% of injected soman
VX, contain a sulfur group and are alkylphosphonothio-
is converted to free pinacolyl-methylphosphonic-acid
lates; they are more toxic and persistent on surfaces than
G-series agents. VX (C 11 H 26 NO 2 PS) is a nonvolatile, within 1 min, and the half-life of this metabolite is less
amber-colored, odorless liquid. than 1 h (Reynolds et al., 1985). Soman is mainly elimi-
nated via enzymatic hydrolysis, in competition with bind-
ing to target acetylcholinesterase (AChE) (HSDB, 2005).
Pharmacokinetics/Toxicokinetics
Nerve agents can be absorbed following ocular exposure, Mechanism of Action
oral ingestion, inhalation, and dermal contact (HSDB,
2005; RTECS, 2006). These nerve agents are absorbed OPs competitively inhibit AChE by binding irreversibly
without producing any irritation or other sensation on the to its esteric site (phosphorylation). Inhibition of the
part of the exposed person or animal. Inhalation of mili- AChE enzyme results in accumulation of acetylcholine
tary nerve agents will have initial effects on the airways (ACh) and excessive stimulation at muscarinic, nicotinic
within seconds. Inhalation of a large amount of the vapor and CNS cholinergic sites. Increased acetylcholine at
will result in sudden loss of consciousness, apnea, flaccid autonomic neuro-effector junctions results in increased
paralysis and seizures within seconds to 2 3 min (Sidell smooth muscle contractions and secretions, but its effect
et al., 1997). Peak effects are seen within 20 30 min and at skeletal muscle junctions is initially stimulatory (fasci-
death is usually due to respiratory failure (Berkenstadt culations), followed by inhibitory (muscle weakness,
et al., 1991). Dermal exposures to nerve agents have a paralysis). The effects on the sino-atrial node of the heart
slower onset of action. Exposure to a large drop or more is inhibitory, causing bradycardia (Namba et al., 1971).
will result in clinical effects within 30 min but with small ACh accumulation in the CNS can cause ataxia, seizures,
drops a delay of up to 18 h can be seen. With ingestion, and coma. These high levels of ACh induce massive neu-
initial symptoms begin in 20 30 min and are usually gas- ronal deaths in various brain areas, particularly in limbic
trointestinal. There is no taste to solutions containing and cortical structures. Death from nerve agents is due to
nerve gas agents (Grob, 1956). paralysis of the diaphragm, airway obstruction from
Distribution in the body is slightly different for each increased tracheobronchial secretions and depression of
of the nerve agents. Distribution of sarin is to the brain, the CNS respiratory center (Garigan, 1996).
liver, kidney, and plasma of mice (Little et al., 1986). VX is also thought to possibly react directly with
Radiolabeled soman was evenly distributed throughout receptors of other neurotransmitters, such as norepineph-
the mouse brain after IV administration, with higher rine, dopamine and GABA. VX appears to have CNS
levels in the hypothalamus (Wolthuis et al., 1986). Tabun effects that are unrelated to AChE activity and these
was also found in high concentrations in the hypothala- agents may produce prolonged effects following convul-
mus after IV administration in mice (Hoskins et al., sive doses (Young et al., 1999).
1986). An unusual feature of soman toxicity is its appar-
ent storage in body “depots” and release over time. This
Toxicity
results in eventual death in animals who survive the initial
dose of soman (Wolthuis et al., 1986). Symptoms of acute exposure to OPs may include musca-
The military nerve agents differ from other OPs in the rinic, nicotinic, and CNS signs. The muscarinic effects
rapidity of “aging” of the OP-enzyme complex. “Aging” include sweating, hypersalivation, bronchoconstriction,
is thought to be due to the loss of an alkyl group, whereby and increased bronchial secretions, miosis, bradycardia,
the inhibitor enzyme complex becomes resistant to reac- hypotension, vomiting and diarrhea, and urinary and fecal
tivation (Young et al., 1999). The half-life (T 1 /2 ) of aging incontinence. The nicotinic effects include fasciculations,
for soman is within minutes, for sarin is about 5 h and for convulsions, and weakness of muscles (including the dia-
both tabun and VX is greater than 40 h (Garigan, 1996). phragm). The CNS effects of nerve agents include rest-
The nerve agents are hydrolyzed by plasma and tissue lessness, anxiety, headaches, seizures, and coma (Garigan,
enzymes to their corresponding phosphoric and phospho- 1996). Effects after inhalation begin within seconds to
nic acids. Oxidative enzymes are also involved in metabo- minutes postexposure. Death can occur within minutes
lism (HSDB, 2005). Sarin is hydrolyzed in the body to from inhibition of AChE function.
isopropyl-methylphosphonic acid (IMPA). IMPA in mice The “G” nerve gases do not readily penetrate intact
studies was generally present at 20-fold higher concentra- skin, but toxicity significantly increases if the skin
tions than sarin in most tissues; exceeding sarin by four becomes permeable. Dermal toxicity of VX is high, even
times in the brain (Little et al., 1986). In mice studies, the through intact skin as the liquid does not evaporate
majority of administered radioactive sarin was detoxified quickly (Berkenstadt et al., 1991; Sidell et al., 1997).