Toxicological Properties of Nerve Agents 

The toxicology of nerve agents, the treatment and prophylaxis of these agents, and a history of human exposures to these agents have been reviewed recently in Marrs, T. C.; Maynard, R. L.; Sidell, F. R., Chemical Warfare Agents: Toxicology and Treatment, John Wiley and Sons: Chichester, 1996, pp. 88-137. This site presents a high level summary of the issues connected with nerve agent toxicity. Interested readers are directed to Marrs, Maynard, and Sidell, and to the 240 references that they cite in their book for a full treatment of this issue.

Nerve Agent Poisoning: Acute Symptoms

The nerve agents (GA, GB, GD, and VX) are all potent inhibitors of esterase enzymes found in the body. The most important of these from a toxicological point of view is acetylcholinesterase. Normally, this enzyme degrades (hydrolyzes) acetylcholine found in the synapses between nerves; acetylcholine transmits signals between nerve cells.



Nerve agents combine with the hydroxyl group of a serine residue of the enzyme, giving an inactive phosphonylated form of the enzyme (shown for GB): ^1,2



When acetylcholinesterase. is inhibited, acetylcholine builds up at the nerve synapses; the accumulation of acetylcholine at these sites effectively prevents the transmission of nerve signals and results in certain characteristic symptoms. ^3-5 Several other esterases in addition to acetylcholinesterase. are phosphonylated by nerve agents, but it is the acetylcholinesterase. inhibition that is responsible for nearly all of the acute symptoms of nerve agent exposure. ²

The first symptoms of nerve agent poisoning to appear are the muscarine-like effects:

• miosis (eye pupil constriction, resulting in dimmed vision)
• frontal headache, eye pain
• runny nose
• anorexia (loss of appetite)
• nausea
• excessive sweating
• tightness in the chest, heartburn

The sequence in which these symptoms appear may vary with route of exposure. If the exposure is sufficiently great, these effects are followed by other muscarine-like symptoms typical of more severe exposure:

• abdominal cramps
• vomiting
• profuse sweating
• dyspnea (shortness of breath)
• diarrhea
• tenesmus (painful, ineffective straining to urinate or defecate)
• drooling and tearing
• urinary frequency
• involuntary urination or defecation
• excessive bronchial secretion

Shortly after the onset of moderate muscarine-like effects, a number of nicotine-like effects ensue:

• fatigue
• mild generalized weakness
• twitching, jerking, and staggering
• cramps
• pallor (paleness)

Central nervous system symptoms of exposure to sublethal doses include:

• tension
• anxiety
• jitteriness
• restlessness
• emotional lability
• giddiness
• insomnia

More extensive exposure leads to:

• headache
• drowsiness
• slowness of recall and confusion

In the cases of nonfatal exposures, many of these effects are reversible upon recovery. More severe central nervous system effects resulting from exposure to nerve agents have not been studied in man. However, accidental exposure to lethal amounts of organophosphate pesticides (which also inhibit acetylcholinesterases) leads progressively to the following symptoms:

• ataxia (lack of muscle control)
• slurred speech
• coma
• areflexia (loss of reflexes)
• Cheyne-Stokes respiration (alternating periods of rapid breathing and not breathing)
• generalized convulsions
• finally, cessation of breathing and death

The effects of nerve agent exposure can be mitigated by the use of antidotes. Selected toxicity values for nerve agents are provided below; please note that this is not an exhaustive review of nerve agent dose-response data.

References

	1.	Burgen, A. S. V.; Hobbiger, S., Br. J. Pharmacol. Chemother., 1951, 6, 593-605.
	2.	Koelle, G. B., Pharmacology and toxicology of organophosphates, in Ballantyne, B.; Marrs, T. C., Eds., Clinical and Experimental Toxicology of Organophosphates and Carbamates, Butterworth-Heinemann: Oxford, 1992, pp. 35-39.
	3.	Grob, D.; Harvey, A. M., Am. J. Med., 1953, 14, 52-63.
	4.	Grob, D., Arch Intern. Med., 1956, 98, 221-239.
	5.	Grob, D.; Harvey, A. M., J. Clin. Invest., 1958, 37, 350-368.

Acute Toxicity of Tabun (GA)

Estimated toxicity values for GA in humans and ranges of experimental toxicity values for GA in animals are given in the table below.

Index	Route of exposure	Species	Value	Reference
Estimated LD 50	percutaneous	man	22 mg kg -1	1
Estimated LD 50	intravenous	man	14 mg kg -1	1
Estimated LCt 50	inhalational	man	150 mg…min m -3	1
Experimental LD 50	percutaneous	mouse	1 mg kg -1	2
		guinea pig	35 mg kg -1	2
Experimental LD 50	intravenous	rabbit	66 mg kg -1	2
		mouse	150 mg kg -1	2
Experimental LCt 50	inhalational	rabbit	4000 mg…min m -3	2
		mouse	220 mg…min m -3	2

Marrs, Maynard, and Sidell provide an extensive tabulation of comparative toxicities for other species and exposure routes. ³

References

	1.	Robinson, J. P., Sci. J., 1967, 3, 33-40.
	2.	Gates, M., Renshaw, B. C., Fluorophosphates and other phosphorus-containing compounds, in Summary technical Report of Division 9, Vol. 1, Parts I, II, Office of Scientific Research and Development: Washington, DC, pp. 131-155.
	3.	Marrs, T. C.; Maynard, R. L.; Sidell, F. R., Chemical Warfare Agents: Toxicology and Treatment, John Wiley and Sons: Chichester, 1996, p. 89-90.

Acute Toxicity of Sarin (GB)

Estimated toxicity values for GB in humans and ranges of experimental toxicity values in animals for GB are given in the table below.

Index	Route of exposure	Species	Value	Reference
Estimated LD 50	percutaneous	man	28 mg kg -1	1
Estimated TD LO	oral	man	2 mg kg -1	2
Estimated LCt 50	inhalational	man	70 mg…min m -3	1
Experimental LD 50	percutaneous	rabbit	0.925 mg kg -1	3
		mouse	1.08 mg kg -1	3
Experimental LD 50	intravenous	rabbit	15 mg kg -1	4
		mouse	113 mg kg -1	5
Experimental LCt 50	inhalational	mouse	150 mg…min m -3	6
		rabbit, guinea pig	1000 mg…min m -3	3

Marrs, Maynard, and Sidell provide an extensive tabulation of comparative toxicities for other species and exposure routes. ⁷

References

	1.	Robinson, J. P., Sci. J., 1967, 3, 33-40.
	2.	Grob, D.; Harvey, A. M., J. Clin. Invest., 1958, 37, 350-368.
	3.	Gates, M., Renshaw, B. C., Fluorophosphates and other phosphorus-containing compounds, in Summary Technical Report of Division 9, Vol. 1, Parts I, II, Office of Scientific Research and Development: Washington, DC, pp. 131-155.
	4.	Wills, J. H., J. Med. Pharmaceut. Chem., 1961, 3, 353-359.
	5.	Schoene, K.; Oldiges, H., Arch. Int. Pharmacodyn. Ther., 1973, 204, 110-123.
	6.	von Lohs, K., Dtch. Gesundheitswesen, 1960, 15, 2179-2183.
	7.	Marrs, T. C.; Maynard, R. L.; Sidell, F. R., Chemical Warfare Agents: Toxicology and Treatment, John Wiley and Sons: Chichester, 1996, p. 89-90.

Acute Toxicity of Soman (GD)

Estimated toxicity values for GD in humans and ranges of experimental toxicity values in animals for GD are given in the table below.

Index	Route of exposure	Species	Value	Reference
Estimated LD 50	percutaneous	man	18 mg kg -1	1
Estimated LCt 50	inhalational	man	70 mg…min m -3	1
Experimental LD 50	intravenous	rat	35-45 mg kg -1	2
		rat	44.5 mg kg -1	3
Experimental LCt 50	inhalational	mice	30 mg…min m -3	4

Marrs, Maynard, and Sidell provide an extensive tabulation of comparative toxicities for other species and exposure routes. ⁵

References

	1.	Robinson, J. P., Sci. J., 1967, 3, 33-40.
	2.	Brezenoff, H. E.; McGee, J.; Knight, V., Acta Pharmacol. Toxicol., 1984, 55, 270-277.
	3.	Padzernik, T. L., et al., Neurotoxicology, 1983, 4, 27-34.
	4.	von Lohs, K., Dtch. Gesundheitswesen, 1960, 15, 2179-2183.
	5.	Marrs, T. C.; Maynard, R. L.; Sidell, F. R., Chemical Warfare Agents: Toxicology and Treatment, John Wiley and Sons: Chichester, 1996, p. 89-90.

Acute Toxicity of VX

Estimated toxicity values for VX in humans and ranges of experimental toxicity values in animals for VX are given in the table below.

Index	Route of exposure	Species	Value	Reference
Estimated LD LO	percutaneous	man	70 mg kg -1	1
Estimated LD 50	intravenous	man	7.5 mg kg -1	2
Estimated LCt 50	inhalational	man	35 mg…min m -3	2
Experimental LD 50	subcutaneous	guinea pig	8.4 mg kg -1	3
		mouse	22 mg kg -1	4

Marrs, Maynard, and Sidell provide an extensive tabulation of comparative toxicities for other species and exposure routes. ⁴

The VX hydrolysis product EA2192 is reported to be almost as toxic as VX itself (intravenous LD ₅₀ of 17 mg kg ^-1 in rabbits ⁵ compared to 8.4 mg kg ^-1 for VX itself in the same species by the same route). Under comparable conditions (22ƒC, pH 13-14), EA2192 has a hydrolysis half-life 3,700 times greater than that of VX. ⁶ EA2192 is thus a particularly long-lived toxic by-product of VX hydrolysis.

References

	1.	WHO Technical Report, Health Aspects of Chemical and Biological Weapons: Report of a World Health Organization Group of Consultants, World Health Organization: Geneva, 1970, pp. 26, 40.
	2.	McNamara, B. P.; Vocci, F. J.; Leitnaker, F. C., Proposed Limits for Human exposure to VX Vapor in Non-Military Operations, Edgewood Arsenal Special Publication EASP 1100-1 (R-1), Department of the Army, July 1973, p. 10.
	3.	Gordon, J. J.; Leadbeater, L., Toxicol. Appl. Pharmacol., 1977, 40, 109-114.
	4.	Marrs, T. C.; Maynard, R. L.; Sidell, F. R., Chemical Warfare Agents: Toxicology and Treatment, John Wiley and Sons: Chichester, 1996, p. 89-90.
	5.	Yang, Y. C.; Szfraniec, L. L.; Beaudry, W. T.; Rohrbaugh, D. K., Oxidative detoxification of phosphonothiolates, J. Am. Chem. Soc., 1990, 112(18), 6621-6627.
	6.	Yang, Y. C.; Szfraniec, L. L.; Beaudry, W. T.; Bunton, C. A., Perhydrolysis of nerve agent VX, J. Org. Chem., 1993, 58, 6964-6965.

Chronic (Longer-Duration) Effects

In addition to the acute anticholinergic effects, two further syndromes involving the neuromuscular system have been associated with organophosphate pesticide poisoning:

• The "intermediate syndrome" consists of weakness of the skeletal musculature and cranial nerve palsies. The onset occurs 1-4 days after acute poisoning, and if respiratory support is provided, recovery occurs within 4-18 days. ¹
• Organophosphate-induced delayed neuropathy (OPIDN) occurs 7-14 days after exposure to organophosphates. In severe cases, it can be a disabling condition characterized by sever muscle weakness and paralysis. ^2-5

Despite an understanding of the syndromes associated with organophosphate exposure and the similarity between nerve agents and organophosphates in mechanisms of action, it is unclear to what extent and magnitude potential long-term effects may occur following exposure to nerve agents.

Marrs, Maynard, and Sidell indicate that histopathological and functional deficits in the central nervous system would probably be observed in survivors of high but sublethal doses of nerve agents. ⁶ They cite several reports of long-term changes associated with exposure to toxic organophosphates both in experimental animals and in humans. ^7-11 They note that whether or not lower (especially sub-convulsive) doses of nerve agents can bring about long-term changes in experimental animals and in humans is less certain. ^12-17 Marrs, Maynard, and Sidell review the evidence for persistent EEG effects, ^7,18,19 and behavioral effects ²⁰ but indicate that the data from these studies are conflicting; they note that further work is required, ⁶ especially to discern possible interrelationships between sub-toxic doses of these agents, stress, other compounds, and permeability of the blood-brain barrier in causing potential clinical effects.

References

	1.	Senanayake, N.; Karalliedde, L., N. Engl. J. Med., 1987, 316, 761-763.
	2.	Anderson, R. J.; Dunham C. B., Arch. Toxicol., 1985, 58, 97-101.
	3.	Johnson, M. K., et al., Fund. Appl. Toxicol., 1985, 5, S180-S181.
	4.	Parker, R. M.; Crowell, J. A.; Bucci, T. J.; Dacre, J. C., Toxicologist, 1988, 8, 248.
	5.	Henderson, J. D.; Higgins, R. J.; Dacre, J. C.; Wilson, B. W., Toxicology, 1992, 72, 117-129.
	6.	Marrs, T. C.; Maynard, R. L.; Sidell, F. R., Chemical Warfare Agents: Toxicology and Treatment, John Wiley and Sons: Chichester, 1996, pp. 93-94.
	7.	Holmes, J. H.; Gaon, M. D., Trans. Am. Clin. Climatol. Assoc., 1956, 68, 86-103.
	8.	Marrs, T. C.; Maynard, R. L., Neurotoxicity of chemical warfare agents, in Vinken, P. J.; Bruyn, G. W.; de Wolff, F. A., Eds., Handbook of Clinical Neurology, Elsevier: Amsterdam, 1994, pp. 233-247.
	9.	Korsak, R. J.; Sato, M. M., Clin. Toxicol., 1977, 11, 83-95.
	10.	Hirshberg, A.; Lerman, Y., Fund. Appl. Toxicol., 1984, 4, S209-S214.
	11.	Rosenstock, L. et al., Lancet, 1991, 338, 223-227.
	12.	Durham, W. F.; Wolfe, H. R.; Quinby, G. E., Arch. Environ. Health, 1965, 10, 55-66.
	13.	Levin, H. S.; Rodnitzsky, R. L., Clin. Toxicol., 1976, 9, 391-405.
	14.	Rodnitzsky, R. L.; Levin, H. S.; Mick, D. L., Arch. Environ. Health, 1975, 30, 98-103.
	15.	Dille, J. R.; Smith, P. W., Aerospace Med., 1964, 35, 475-478.
	16.	Gershon, S.; Shaw, F. H., Lancet, 1961, 1, 1371-1374.
	17.	Maizlish, N. et al., Am. J. Ind. Med., 1987, 12, 153-172.
	18.	Duffy, F. H., et al., Toxicol. Appl. Pharmacol., 1979, 47, 161-176.
	19.	Burchfiel, J. L.; Duffy, F. H.; van Sim, M., Toxicol. Appl. Pharmacol., 1976, 35, 365-379.
	20.	McDonough, J. H.; Smith, R. F.; Smith, C. D., Neurobehav. Toxicol. Teratol., 1986, 8, 179-187.