Effects of SKF 525A,Phenobarbital,and 3-Methylcholanthrene on Ethylene Dichloride Toxicity Following Inhalation Exposure

Abstract

The effect of cytochrome P-450-dependent metabolism on ethylene dichloride (EDC) toxicity was investigated in mice. Prior to exposure to EDC, groups of male CD-1 mice were pretreated with phenobarbital or 3-methylcholanthrene to induce metabolism. Other mice were administered SKF 525A before EDC exposure to inhibit cytochrome P-450 metabolism. Following the different pretreatments, mice were exposed to EDC at selected concentrations (1000 ppm, 1250 ppm, or 1500 ppm). Exposure to EDC, without pretreatment, produced a dose-dependent increase in mortality at 24 and 48 hours postexposure. This response was enhanced at all concentrations of EDC by phenobarbital pretreatment and attenuated by the administration of SKF 525A. Pretreatment with 3-methylcholanthrene prior to EDC exposure at 1000 ppm also produced an increase in mortality as compared to EDC exposure without pretreatment. Exposure to EDC was associated with an increased kidney weight:body weight ratio. SKF 525A pretreatment prevented the increase in the kidney weight:body weight ratio at an EDC exposure concentration of 1000 ppm. Pathological changes produced in the kidneys of mice exposed to EDC were decreased by SKF 525A pretreatment. These results support the hypothesis that a product of the cytochrome P-450-dependent metabolism of EDC is involved in the toxicity produced following acute inhalation exposure to this chemical.

References

1. IARC (INTERNATIONAL AGENCY FOR RESEARCH ON CANCER) . (1979). Monograph on the evaluation of carcinogenic risk of chemicals to humans. Vol. 20, Ethylene dichloride. Lyon: International Agency for Research on Cancer, pp. 429–442.

2. NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH. (1976). Criteria for a recommended standard. Occupational exposure to ethylene dichloride. HEW Publication No. (NIOSH) 76–139.

3. Parker, J.C. , Casey, G.E. , Bahlman, L.J. , Leidel, N.A. , Rose, D. , Stein, H.P. , Thomas, A.W. , and Lane, J.M. (1979). Chloroethanes: Review of toxicity. Am. Ind. Hyg. Assoc. J. 40, A46–A57.

4. Davidson, I.W.F. , Sumner, D.D. , and Parker, J.C. (1982). Ethylene dichloride: A review of its metabolism, mutagenic and carcinogenic potential. Drug Chem. Toxicol. 5(4), 319–388.

5. Heppel, L.A. , Neal, P.A. , Perrin, T.L. , Endicott, K.M. , and Porterfield, V.T. (1945). Toxicology of 1,2-dichloroethane. III. Its acute toxicity and the effect of protective agents. J. Pharmacol. Exp. Ther. 83, 53–63.

6. Heppel, L.A. , Neal, P.A. , Perrin, T.L. , Endicott, K.M. , and Porterfield, V.T. (1946). Toxicology of 1,2-dichloroethane. V. Effects of daily inhalations. J. Ind. Hyg. Toxicol. 28, 113–120.

7. Spencer, H.C. , Rowe, V.K. , Adams, E.M. , McCollister, D.D. , and Irish, D.D. (1951). Vapor toxicity of ethylene dichloride determined by experiments on laboratory animals. Arch. Ind. Hyg. Occup. Med. 4, 482–493.

8. Francovitch, R.J. , and George, W.J. (1985). A dual function exposure system for acute exposure of mice to chemical vapors. J. Am. Coll. Toxicol. 4(1), 63–69.

9. White, L.D. , Taylor, D.G. , Mauer, P.A. , and Kupel, R.E. (1970). A convenient optimized method for the analysis of selected solvent vapors in the industrial atmosphere. Am. Ind. Hyg. Assoc. J. 31, 225–232.

10.

10. Lock, E.A. , and Ishmael, J. (1981). Hepatic and renal nonprotein sulfhydryl concentration following toxic doses of hexachloro-1,3-butadiene in the rat: The effect of aroclor 1254, phenobarbitone, or SKF 525A treatment. Toxicol. Appl. Pharmacol. 57, 79–87.

11.

11. Guengerich, F.P. (1977). Separation and purification of multiple forms of microsomal cytochrome P-450: Activities of different forms of cytochrome P-450 toward several compounds of environmental interest. J. Biol. Chem. 252, 3970–3979.

12.

12. Anders, M.W. (1971). Enhancement and inhibition of drug metabolism. Annu. Rev. Pharmacol. Toxicol. 11, 37–56.

13.

13. Banerjee, S. , and Van Duuren, B.L. (1979). Binding of carcinogenic halogenated hydrocarbons to cell macromolecules. J. Natl. Canc. Inst. 63(3), 707–711.

14.

14. Guengerich, F.P. , Crawford, W.M. , Domoredzki, J.Y. , MacDonald, T.L. , and Watanabe, P.G. (1980). In vitro activation of 1,2-dichloroethane by microsomal and cytosolic enzymes. Toxicol. Appl. Pharmacol. 55, 303–317.

15.

15. Yllner, S. (1971). Metabolism of 1,2-dichloroethane-14C in the mouse. Acta Pharmacol. Toxicol. 30, 257–265.

16.

16. McCall, S.N. , Jurgens, P. , and Ivanetich, K.M. (1983). Hepatic microsomal metabolism of the diloroethanes. Biochem. Pharmacol. 32(2), 207–213.

17.

17. Ambrose, A.M. (1950). Toxicological studies of compounds investigated for use as inhibitors of biological processes. II. Toxicity of ethylene chlorhydrin. Arch. Ind. Hyg. Occup. Med. 2, 591–597.

18.

18. Hayes, F.D. , Short, R.D. , and Gibson, J.E. (1973). Differential toxicity of monochloroacetate, monofluoroacetate, and monoiodoacetate in rats. Toxicol. Appl. Pharmacol. 26, 93–102.

19.

19. Yllner, S. (1971). Metabolism of chloroacetate-1-14C in the mouse. Acta Pharmacol. Toxicol. 30, 69–80.

20.

20. Johnson, M.K. (1965). The influence of some aliphatic compounds on rat liver glutathione levels. Biochem. Pharmacol. 14, 1383–1385.

21.

21. Johnson, M.K. (1966). Studies on glutathione S-alkyltransferase of the rat. Biochem. J. 98, 44–56.

22.

22. Johnson, M.K. (1967). Metabolism of chloroethanol in the rat. Biochem. Pharmacol. 16, 185–199.

23.

23. Heppel, L.A. , Porterfield, V.T. , and Sharpliss, N.G. (1947). Toxicology of 1,2-dichloroethane. IV. Its detoxification by l-cysteine, dl-methionine, and other sulfur-containing compounds. J. Pharmacol. Exp. Ther. 91, 385–394.

24.

24. Hefner, R.E. , Watanabe, P.G. , and Gehring, P.J. (1975). Preliminary studies of the fate of inhaled vinyl chloride monomer in rats. Ann. NY Acad. Sci. 246, 135–148.

25.

25. Jaeger, R.J. , Conolly, R.B. , and Murphy, S.D. (1974). Effect of 18 hr fast and glutathione depletion on 1,1-dichloroethylene induced hepatotoxicity and lethality in rats. Exp. Molec. Pathol. 20, 187–198.

26.

26. Brown, B.R. , Sipes, I.G. , and Sagalyn, A.M. (1974). Mechanisms of acute hepatic toxicity: Chloroform, halothane, and glutathione. Anaesthesiology 41, 554–561.