Despite extensive research efforts, there is no unanimous approval of any animal model to evaluate the toxicity of sulphur mustard [SM; bis (2-chloroethyl) sulphide] or nitrogen mustard [HN-3; tris-(2-chloroethyl) amine] and screening of various prophylactic and therapeutic agents against them. In this study, differential toxicity of mustard agents in higher animal model that is male rabbit was determined. Protective efficacy of DRDE 07 [S-2(2-aminoethylamino) ethyl phenyl sulphide] and its analogues were also evaluated against SM and HN-3 toxicity. Differential toxicity study of SM and HN-3 reveals that both the compounds were more toxic by percutaneous route as compared to subcutaneous route. Till date, there is no recommended drug to counteract SM induced toxicity or mortality in vivo. However, DRDE 07 (an amifostine analogue) and its analogues are found to be very effective protective agents against percutaneously exposed SM in rabbits. The present experiments also showed that SM does not cause skin injury alone but also can cause systemic toxicity as well. DRDE 07 and many of its analogues may prove as prototype compounds for the development of better prophylactic and therapeutic drugs to counter the toxicity of SM or HN-3. In conclusion, rodents and rabbits can be used for the screening of drugs against the blistering agents.
Black RM, Clarke RJ, Read RW, Reid MTJ.Application of gas chromatography-mass spectrometry and gas chromatography-tandem mass spectrometry to the analysis of chemical warfare samples, found to contain residues of the nerve agent sarin, sulfur mustard and their degradation products . J Chromatogr1994; 662: 301-321.
3.
Croddy E.Urban terrorism: chemical warfare in Japan. Jane’s Intelligence Rev1995; 7: 520-523.
4.
Goozner B., Lutwick LI, Bourke E.Chemical terrorism: a primer for2002. J Assoc Acad Minor Phys2002; 13: 14-18.
5.
Renshaw B.Mechanisms in production of cutaneous injuries by sulfur and nitrogen mustards . In: Chemical warfare agents and related chemical problems : report of division9, Washington, DC: National Defence Research Committee , 1946.
6.
Dannenberg AM Jr, Pula PJ, Liu LH, et al. Inflammatory mediators and modulators released in organ culture from rabbit skin lesions produced in vivo by sulfur mustard. I. Quantitative histopathology; PMN, basophil, and mononuclear cell survival; and unbound (serum) protein content. Am J Pathol1985; 121: 15-27.
Wormser U., Nyska A.Protective effect of ophenanthroline against mechlorethamine toxicity in the rat liver slice system and in the guinea pig skin. Arch Toxicol1991; 65: 666-670.
9.
Chauhan RS, Murthy LVR, Malhotra RCEffect of sulphur mustard on mouse skin: an electron microscope evaluation . Bull Environ Contamin Toxicol1993; 51: 374-380.
Cowan FM, Yourick JJ, Hurst CG, Broomfield CA, Smith WJSulfur mustard-increased proteolysis following in vitro and in vivo exposures . Cell Biol Toxicol1993; 9: 269-277.
12.
Riviere JE, Brooks JD, Williams PL, Monteiro-Riviere NAToxicokinetics of topical sulfur mustard penetration, disposition, and vascular toxicity in isolated perfused porcine skin. Toxicol Appl Pharmacol1995; 135: 25-34.
13.
Fort Mc Clellan.Potential military chemical/biological agents and compounds. FM 3-9 NAVFAC P-467 AFR. AL: Headquarters, Department of Army, Navy and Air Force, 1990, p.355-357.
14.
Sharma M., Vijayaraghavan R., Ganeshan K.Comparison of toxicity of selected mustard agents by percutaneous and subcutaneous routes. Ind J Exper Biol2008; 46: 822-830.
15.
Mattes WB, Hartley JA, Kohn KWDNA sequence selectivity of guanine-N7 alkylation by nitrogen mustards . Nucleic Acid Res1986; 14: 2971-2987.
16.
Casillas RP , Kiser RC, Truxall JA, et al. Therapeutic approaches to dermatotoxicity by sulfur mustard. I. Modulation of sulfur mustard induced cutaneous injury in the mouse ear vesicant model. J Appl Toxicol2000; 20: S145-S151.
17.
Papirmeister B., Feister AJ, Robinson SI, Ford RDMustard gas: toxic mechanisms and pharmacological implications. Boca Raton FL: CRC Press, 1991.
18.
Sawyer TWModulation of sulfur mustard toxicity by arginine analogues and related nitric oxide synthase inhibitors in vitro. Toxicol Sci1998; 46: 112-121.
19.
Sawyer TWCharacterization of the protective effects of L-nitroarginine methyl ester (L-NAME) against the toxicity of sulfur mustard in vitro. Toxicology1988; 131: 21-32.
20.
Sawyer TW, Lundy PM, Weiss MTProtective effect of an inhibitor of nitric oxide synthase on sulfur mustard toxicity in vitro. Toxicol Appl Pharmacol1996; 141: 138-144.
21.
Sawyer TW, Risk D.Effects of selected arginine analogues on sulfur mustard toxicity in humanand hairless guinea pig skin keratinocytes. Toxicol Applied Pharmacol2000; 163: 75-85.
22.
Joshi U., Raza SK, Kumar P., Vijayaraghavan R., Jaiswal DKA process for preparation of S-(ω-aminoalkylamino) alkyl aryl sulphide dihydrochloride. Indian Patent Filed, Patent Office , New Delhi, India, 1999.
23.
Bhattacharya R., Lakshmana Rao PV, Pant SC, et al. Protective effects of amifostine and its analogues on sulphur mustard toxicity in vitro and in vivo. Toxicol Appl Pharmacol2001 ; 176: 24-33.
24.
Pathak U., Raza SK, Kulkarni AS, Vijayaraghavan R., Kumar P., Jaiswal DKNovel S-substituted aminoalkyl amino ethanethiols as potential antidotes against sulphur mustard toxicity. J Med Chem2004; 47: 3817-3822.
25.
Vijayaraghavan R., Kumar P., Joshi U., et al. Prophylactic efficacy of amifostine and its analogues against sulphur mustard toxicity . Toxicology2001; 163: 83-91.
26.
Kumar P., Vijayaraghavan R., Kulkarni AS, Pathak U., Raza SK, Jaiswal DK In vivo protection by amifostine and DRDE-07 against sulphur mustard toxicity . Human Exper Toxicol2002; 21: 371-376.
27.
Kulkarni AS , Vijayaraghavan R., Gautam A., et al. Evaluation of analogues of DRDE-07 as prophylactic agents against the lethality and toxicity of sulphur mustard administered through percutaneous route. J Appl Toxicol2006; 26: 115-125.
28.
Gad SC, Weil CSStatistics for toxicologists. In: Hayes AW (ed.). Principles and methods of toxicology. 2nd ed. Raven Press, New York, p.463-467.
29.
Vijayaraghavan R., Kulkarni AS, Pant SC, et al. Differential toxicity of sulfur mustard administered through percutaneous, subcutaneous and oral routes. Toxicol Appl Pharmacol2005; 202: 180-188.
30.
Rao PVL , Vijayaraghavan R., Bhaskar ASB.Sulphur mustard induced DNA damage in mice after dermal and inhalation exposure. Toxicology1989; 139: 39-51.
31.
Wormser U., Sintov A., Brodsky B., Casillas RP, Nyska A.Protective effect of topical iodine containing antiinflammatory drugs against sulphur mustard induced skin lesions. Arch Toxicol2004; 78; 156-166.
32.
Casbohm SL, Rogers JV, Stonerock MK, et al. Localization of substance P gene expression for evaluating protective countermeasure against sulphur mustard. Toxicology2004; 204: 229-239.
33.
Hambrook JL , Howells DJ, Schock C.Biological fate of sulphur mustard (1,1’-thiobis(2-chloroethane)): uptake, distribution and retention of 35S in skin and in blood after cutaneous application of 35S mustard in rat and comparison with human blood in vitro . Xenobiotica1999; 23: 537-561.
34.
Spencer CM, Goa KLAmifostine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential as a radioprotector and cytotoxic chemoprotector . Drugs1995; 50: 1001-1031.
35.
Capizzi RLThe preclinical basis for broad spectrum selective cytoprotection of normal tissues from cytotoxic therapies by amifostine. Seminars Oncology1999; 26: 3-21.
36.
Hospers GA, Eisenhauer EA, de Vries EGThe sulfhydryl containing compounds WR-2721 and glutathione as radio and chemoprotective agents. A review, indications for use and prospects. Br J Cancer1999; 80: 629-638.
