DNA adducts: effects of low exposure to ethylene oxide, vinyl chloride andbutadiene

Dose-response relationships of genotoxic agents differ greatly depending on the agent and the endpoint being evaluated. Simple conclusions that genoto xic effects are linear cannot be applied universally. The shape of the mole cular dose of DNA adducts varies from linear, to supralinear, to sublinear depending on metabolic activation and detoxication, and repair of individua l types of DNA adducts. For mutagenesis and other genotoxicity endpoints, t he dose-response reflects the molecular dose of each type of DNA adduct, ce ll proliferation, as well as endogenous factors that lead to mutagenesis su ch as the formation and repair of endogenous DNA adducts. These same factor s are important when interpreting the shape of dose-response data for carci nogenesis of genotoxic agents, however, tumor background variability adds a dditional complexity. Endogenously formed DNA adducts may be identical to t hose formed by chemicals, as in the case of vinyl chloride and ethylene oxi de, or they may be those associated with oxidative stress. Data presented i n 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 tha t present as a steady-state amount in unexposed control rats. Similar data are shown for ethylene oxide. Extremely sensitive methods have been develop ed for measuring the molecular dose of genotoxins. These methods can detect DNA adducts as low as 1 per 10(9) to 10(10). However, in view of the high number of endogenous DNA adducts that are present in all cells, it is unlik ely 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. (C) 2000 Elsevie r Science B.V. All rights reserved.