Archives of Toxicology

, Volume 39, Issue 1–2, pp 7–12 | Cite as

Metabolic activation of chlorinated ethylenes: dependence of mutagenic effect on electrophilic reactivity of the metabolically formed epoxides

  • D. Henschler
  • G. Bonse
Session I: Structure-Activity Relationship Linking Matabolism of Foreign Compounds to Toxic Effects


In chlorinated ethylenes, the chlorine substitution exerts, by its electron withdrawal effect, a stabilization of the molecule which increases with the number auf chlorine residues. All chlorinated ethylenes are metabolically transformed, in a first step reaction, to epoxides which may rearrange to aldehydes or acyl chlorides, respectively, undergo hydrolysis to diols, conjugate with glutathione, or react, by alkylation, with cellular macromolecules. The electrophilicity of the epoxides is high with those having an unsymmetric chlorine substitution, and comparatively low with the others bearing symmetric chlorine residues. According to in vitro mutagenicity testing in a modified Ames system, the following rule on structure/activity-relationship has been worked out: mutagenic potential is bound to unsymmetric substitution and high chemical reactivity (as with vinyl chloride, vinylidene chloride, and trichloroethylene), symmetric substitution results in lower chemical reactivity and non-mutagenicity. So far, the rule is substantiated by positive carcinogenic effects in animal experiments with vinyl chloride, vinylidene chloride and trichloroethylene.

Key words

Mutagenicity Carcinogenicity Chlorinated ethylenes Epoxides Bioactivation 


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  1. Bartsch, H., Malaveille, C., Montesano, R.: Human, rat and mouse liver-mediated mutagenicity of vinyl chloride in S. typhimurium strains. Int. J. Cancer 15, 429 (1975)Google Scholar
  2. Bonse, G., Henschler, D.: Chemical reactivity, biotransformation and toxicity of polychlorinated aliphatic compounds. CRC Crit. Rev. Toxicol. 4, 395 (1976)Google Scholar
  3. Bonse, G., Urban, Th., Reichert, D., Henschler, D.: Chemical reactivity, metabolic oxirane formation and biological reactivity of chlorinated ethylenes in the isolated perfused rat liver preparation. Biochem. Pharmacol. 24, 1829 (1975)Google Scholar
  4. Butler, T. C.: Metabolic transformation of Tri. J. Pharmacol. Exp. Ther. 97, 84 (1949)Google Scholar
  5. Daniel, J. W.: The metabolism of 36Cl-labelled trichloroethylene and tetrachloroethylene in the rat. Biochem. Pharmacol. 12, 795 (1963)Google Scholar
  6. Department of Health, Education, Welfare, Washington, D.C. Memorandum, March 20, 1975Google Scholar
  7. Greim, H., Bonse, G., Radwan, Z., Reichert, D., Henschler, D.: Mutagenicity in vitro and potential carcinogenicity of chlorinated ethylenes as a function of metabolic oxirane formation. Biochem. Pharmacol. 24, 2013 (1975)Google Scholar
  8. Henschler, D., Bonse, G., Greim, H.: Carcinogenic potential of chlorinated ethylenes — tentative molecular rules. In: Environmental pollution and carcinogenic risk. INSERM Symposia Series 52, 171 (1976)Google Scholar
  9. Leibman, K. C., Ortiz, E.: Microsomal metabolism of chlorinated ethylenes. 6th Int. Congr. Pharmacol., Helsinki, Abstr. 257, Nr. 608 (1975)Google Scholar
  10. Maltoni, C.: Report at International PVDC Seminar, Hamburg 26. 1. 1977Google Scholar
  11. Maltoni, C., Lefemine, G.: Carcinogenicity bioassays of vinyl chloride. I. Research plan and early results. Environm. Res. 7, 387 (1974)Google Scholar
  12. Rannug, U., Johansson, A., Ramel, C., Wachtmeister, C. A.: The mutagenicity of vinyl chloride after metabolic activation. Ambio 3, 194 (1974)Google Scholar
  13. I.A.R.C. Intern. Tech. Report 75/001: Report of a working group on epidemiological studies on vinyl chloride exposed People. Lyon (1975)Google Scholar
  14. Williamson, D. G., Cvetanovic, R. J.: Rates of reactions of ozone with chlorinated and conjugated olefines. J. Amer. chem. Soc. 90, 4248 (1968)Google Scholar

Copyright information

© Springer-Verlag 1977

Authors and Affiliations

  • D. Henschler
    • 1
  • G. Bonse
    • 1
  1. 1.Institut für ToxikologieUniversität WürzburgWürzburgFederal Republic of Germany

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