DNA adducts: Effects of low exposure to ethylene oxide, vinyl chloride and butadiene

James A. Swenberg, Amy Ham, Hasan Koc, Eric Morinello, Asoka Ranasinghe, Natalia Tretyakova, Patricia B. Upton, Kuen Yuh Wu

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Dose-response relationships of genotoxic agents differ greatly depending on the agent and the endpoint being evaluated. Simple conclusions that genotoxic effects are linear cannot be applied universally. The shape of the molecular dose of DNA adducts varies from linear, to supralinear, to sublinear depending on metabolic activation and detoxication, and repair of individual types of DNA adducts. For mutagenesis and other genotoxicity endpoints, the dose-response reflects the molecular dose of each type of DNA adduct, cell proliferation, as well as endogenous factors that lead to mutagenesis such as the formation and repair of endogenous DNA adducts. These same factors are important when interpreting the shape of dose-response data for carcinogenesis of genotoxic agents, however, tumor background variability adds additional complexity. Endogenously formed DNA adducts may be identical to those formed by chemicals, as in the case of vinyl chloride and ethylene oxide, or they may be those associated with oxidative stress. Data presented in this paper demonstrate that the exogenous number of adducts induced by 5 days of exposure to 10 ppm vinyl chloride is only 2.2-fold greater than that present as a steady-state amount in unexposed control rats. Similar data are shown for ethylene oxide. Extremely sensitive methods have been developed for measuring the molecular dose of genotoxins. These methods can detect DNA adducts as low as 1 per 109 to 1010. However, in view of the high number of endogenous DNA adducts that are present in all cells, it is unlikely that causal relationships can be attributed to very low numbers of such DNA adducts. Effects of both exogenous and endogenous DNA adducts need to be factored into the interpretation of chemical exposures. Copyright (C) 2000 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)77-86
Number of pages10
JournalMutation Research - Genetic Toxicology and Environmental Mutagenesis
Volume464
Issue number1
DOIs
StatePublished - Jan 3 2000

Bibliographical note

Funding Information:
This research was supported in part by grants from the Chemical Manufacturers Association, the EPA/NIEHS Superfund Basic Research Program (P42-ES05948) and NIEHS Training Grants (ES07126, ES07017 and ES05779).

Keywords

  • Butadiene
  • DNA adducts
  • Ethylene oxide
  • Low dose
  • Molecular dose
  • Occupational exposure
  • Risk assessment
  • Vinyl chloride

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