Toxicological Properties of Vesicants 

The toxicology of and treatment for exposure to mustard have been recently reviewed in Marrs, T. C.; Maynard, R. L.; Sidell, F. R., Chemical Warfare Agents: Toxicology and Treatment, John Wiley and Sons: Chichester, 1996, pp. 144-173. This site presents a high level summary of the issues connected with mustard toxicity. Interested readers are directed to Marrs, Maynard, and Sidell, and to the 69 works that they cite in their book for a full treatment of this issue.

The toxicity of chemical warfare agents should not be judged simply on the basis of lethal doses or exposures. Mustard provides a case in point; during World War I, it was a very effective incapacitating agent, despite producing only 1 percent fatalities among its casualties. ¹

Chemical weapons disperse mustard as an aerosol, which then evaporates to give vapor contamination. Exposure to aerosol droplets of mustard or mustard vapor causes no immediate effect. Itching, burning, and inflammation of areas where it contacts the skin generally begin about 4 hours after exposure (the exact length of time depends on the amount of agent involved), followed by swelling of the tissue. After 20 to 24 hours small blisters form around the periphery of the affected area. Finally, fully developed blisters fill with a colorless to yellow liquid. Severe tissue degeneration occurs within the blisters, which are vulnerable to infection; the wound may take several months to heal. Inhalation of mustard vapor in high enough quantities leads to similar lesions in the lung and pulmonary edema. ^2,3

The hydrolysis products of H are also reported to exhibit toxicity. ⁴ However, thiodiglycol (2,2'-thiobis[ethanol]), the major breakdown product, exhibits low toxicity. Therefore, it is likely that the majority of the toxic effects attributed to the hydrolysis products are due to unreacted mustard and bis(chloroethyl)polysulfides present in the original material.

Selected indices of toxicity for mustard gas are presented below. Note that exposure values are in many cases given in ranges, because the effect of a given exposure on skin depends on the ambient temperature.

Index	Route of exposure	Species	Value	Reference
Estimated LCt 50	inhalational	man (healthy male military personnel)	900 mg min m -3	16
Estimated LCt 50	percutaneous	man (healthy male military personnel)	5,000 mg min m -3	16
Estimated ECt 50	inhalational	man (healthy male military personnel)	25-100 mg min m -3	16
Estimated ECt 50	percutaneous	man (healthy male military personnel)	25-500 mg min m -3	16
ICt 50 for erythema	percutaneous	man	100-400 mg min m -3	2
ICt 50	ocular	man	200 mgÖmin m -3	2
ICt 50 for blistering	percutaneous	man	200-1,000 mg min m -3	2
ICt 50 for severe skin burns	percutaneous	man	750-1,000 mg min m -3	2
Estimated LD 50	percutaneous	man (healthy male military personnel)	20 mg kg -1	16
Estimated ED 50	percutaneous	man (healthy male military personnel)	9 mg kg -1	16
TD LO for erythema	percutaneous	man	50 mg cm -2 (5 minutes)	3
TD LO for blistering	percutaneous	man	500 mg cm -2 (5 minutes)	3
Experimental LD 50	percutaneous	rats	9 mg kg -1	7
		rabbits	100 mg kg -1	7
Experimental LCt 50	inhalational	dog	600 mgÖmin m -3	2
		goats	1,900 mgÖmin m -3	2

Chronic (longer duration) mental effects of mustards have been reported. ⁸ However, the most notable long-term effect of exposure to mustard gas has been suggested to be cancer of the upper respiratory tract, which has been observed in a population of several thousand former mustard gas production workers at Okunojima, ^9-11 British mustard gas workers in Cheshire, ¹² and American World War I veterans. ^13-14 There is also some evidence that exposure to very high levels can cause lung cancer. ^9-13 DNA cross-linking is likely responsible for the carcinogenicity associated with mustard gas exposure.

Biochemically, it is well established that mustard agents are bifunctional alkylating agents. They react with nucleic acids, predominantly via N-7 alkylation of guanine residues, which disrupts normal DNA functioning. The mechanism for this alkylation is similar to the mechanism observed for mustard hydrolysis.

 

Twenty-five percent of alkylations leads to interstrand cross linking of DNA: ¹⁵

 

There is no known antidotefor exposure to mustard agent.

References:
1. Prentiss, A. M., Chemicals in war; a treatise on chemical warfare, McGraw-Hill Book Company, Inc.: New York, 1937, p. 180.
2. Gates. M.; Moore, S., Mustard gas and other sulfur mustards, in Summary Technical Report of Division 9, Vol. 1, Parts I, II, Office of Scientific Research and Development: Washington, DC, pp. 30-58.
3. NATO Handbook on the Medical Aspects of NBC Defensive Operations, Part III Chemical, AMedP-6, 1985.
4. D'Agostino, P. A.; Provost, L. R., The Identification of Compounds in Mustard Hydrolysate (U), DRES Suffield Report 412, Ralston, Alberta, Canada, 1985, available through DTIC AD-A156381.
5. Vedder, E. B., The Medical Aspects of Chemical Warfare, Williams and Wilkins: Baltimore, 1925, p. 128.
6. Prentiss, p. 14.
7. Marrs, T. C.; Maynard, R. L.; Sidell, F. R., Chemical Warfare Agents: Toxicology and Treatment, John Wiley and Sons: Chichester, 1996, p. 145.
8. Marrs, Maynard, and Sidell, p. 161.
9. Wada, S. et al., Y., Lancet, 1968, 1, 1161-1163.
10. Nishimoto, Y. et al., Epidemiological status of lung cancer in Japanese mustard gas workers, in Miller, R. W. et al., Eds., Unusual Occurrences as Clues to Cancer Etiology: proceedings of the 18th International Symposium of the Princess Takamatsu Cancer Research Fund, Tokyo, 1987, Taylor and Francis: Tokyo, 1988, pp. 95-101.
11. Yanagida, J. et al., Jpn. J. Cancer Res., 1988, 79, 1276-1283.
12. Easton, D. F.; Peto, J.’ Doll, R., Br. J. Ind. Med., 1988, 45, 652-659.
13. Beebe, G. W., J. Natl. Cancer Inst., 1960, 25, 1231-1251.
14. Norman, J. E., J. Natl. Cancer Inst., 1975, 54, 311-317.
15. Fox, M.; Scott, D., Mutat. Res., 1980, 75, 131-168.
16. Review of Acute Human-Toxicity Estimates for Selected Chemical-Warfare Agents, Committee on Toxicology, National Research Council: Washington, 1997, pp. 59-64.


Lewisite (L)

The toxicology of and treatment for exposure to Lewisite have been recently reviewed in Marrs, T. C.; Maynard, R. L.; Sidell, F. R., Chemical Warfare Agents: Toxicology and Treatment, John Wiley and Sons: Chichester, 1996, pp. 175-182. This site presents a high level summary of the issues connected with Lewisite toxicity. Interested readers are directed to Marrs, Maynard, and Sidell, and to the 24 works that they cite in their book for a full treatment of this issue.

The various symptoms associated with exposure to Lewisite range in severity and time of appearance during the course of exposure. Eye pain and inflammation can result from ocular exposures. Exposure of the skin to Lewisite produces an immediate pain and symptoms similar to second and third degree burns. Lewisite diffuses more rapidly into skin than does mustard. Erythema generally appears within 30 minutes of exposure, followed by blistering within 4 to 24 hours. Relative to mustard, healing occurs more rapidly and the risk of secondary infection is less following Lewisite exposure.

Selected indices of toxicity for Lewisite are presented below.

Index	Route of exposure	Species	Value	Reference
maximum tolerable exposure	–	man	0.8 mg m -3	1
TD LO for erythema	percutaneous	man	0.05-0.10 mg cm -2	2
TD LO for blistering	percutaneous	man	0.2 mg cm -2	2
ICt 50	ocular	man	150 mg min m -3	2
Estimated LCt 50	inhalational	man	1,500 mgÖmin m -3	3,4
			2,500 mgÖmin m -3	2
Experimental LD 50	percutaneous	rabbits	5.3 mg kg -1	5
		rats	24 mg kg -1	6
Experimental LCt 50	inhalational	guinea pigs	470 mgÖmin m -3	4
		mice	2,800 mgÖmin m -3	4

Price and von Limbach report toxic doses of Lewisite for various fish species and tadpoles of 0.2-2.0 ppm. ⁷

In the body, the arsenic atom in Lewisite is capable of reacting with adjacent thiol groups in proteins to form -S-As-S- ring structures. Both sodium arsenite and Lewisite bind reversibly with enzymes containing thiol groups, ⁸ suggesting that the toxicity of Lewisite may be the result of enzymatic inhibition. However, recent work has also suggested that Lewisite toxicity may be due to some other toxic property possessed by Lewisite but not by inorganic arsenic. ⁹ The immediate hydrolysis products of Lewisite, ClÇCH=CHÇAs(OH) ₂ and ClÇCH=CHÇAs=O, are also reported to be vesicants. ¹⁰ Based on the rapid hydrolysis rate of Lewisite, it seems quite possible that the hydrolysis products are responsible in vivo for the effects associated with Lewisite exposure. Lewisite and its hydrolysis products eventually produce various organic and inorganic arsenic species.

The effects of Lewisite exposure can be mitigated by the use of antidote.

References:
1. Prentiss, A. M., Chemicals in war; a treatise on chemical warfare, McGraw-Hill Book Company, Inc.: New York, 1937, p. 18.
2. Goldman, M., Dacre, J. C., Rev. Environ. Contam. Toxicol., 1989, 110, 75-115.
3. Prentiss, p. 14.
4. Gates, M.; Williams, J. H.; Zapp, J. A., Arsenicals, in Summary Technical Report of Division 9, Vol. 1, Parts I, II, Office of Scientific Research and Development: Washington, DC, pp. 83-114.
5. Inns, R. H.; Rice, P., Human Exp. Toxicol., 1993, 12, 241-246.
6. Cameron, G. R.; Carleton, H. M; Short, R. H. D., J. Pathol. Bacteriol., 1946, 58, 411-422.
7. Price, C. C.; von Limbach, B., Further Data on the Toxicity of Various CW Agents to Fish, OSRD No. 5528, Division 9, National Defense Research Committee of the Office of Scientific Research and Development, 1945.
8. Stocken, L. A.; Thompson, R. H. S., Biochem. J., 1946, 40, 529-535.
9. Inns, R. H.; Bright, J. E., Marrs, T. C., Toxicology, 1988, 51, 213-222.
10. Waters, W. A.; Williams, J. H., J. Chem. Soc. 1950, 18-22.