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1100 ppm vinyl chloride for 5 days or 4 wk. The number of adductsincreased in a supralinear manner. Exposure to 10 ppm vinyl chloride for 5days caused a 2- to 3-fold incr in epsilon G over that of the controls,while 4 wk exposure resulted in a 5-fold incr. This was confirmed with[13C2]vinyl chloride & by measuring exogenous & endogenous adductsin the same animals. Exposure to 100 ppm vinyl chloride for 4 wk caused a25-fold incr in epsilon G levels over that found in control rats, whileexposure to 1100 ppm resulted in a 42-fold incr. The amount of endogenousepsilon G was similar in liver DNA from rats & humans. A comparableresponse to exposure was seen in rats & mice exposed to 0, 25, 250 or2500 ppm vinyl fluoride for 12 months. There was a very high correlationbetween epsilon G levels in rat & mouse liver at 12 months & theincidence of haemangiosarcoma at 2 yr. /The authors/ were able todemonstrate that the target cell population for angiosarcoma, thenonparenchymal cells, contained more epsilon G than hepatocytes, eventhough nonparenchymal cells are exposed by diffusion of vinyl halidemetabolites formed in hepatocytes. The expression of N-methylpurine-DNAglycosylase mRNA was induced in rat liver after exposure to either 25 or2500 ppm vinyl fluoride. When this induction was investigated inhepatocytes & nonparenchymal cells, it was found that the latter hadonly 20% of the N-methylpurine-DNA glycosylase mRNA of hepatocytes, &that only the hepatocytes had induction of this expression after exposureto vinyl fluoride. Thus, the target cells for vinyl halide carcinogenesishave much lower expression of this DNA repair enzyme, which has beenassociated with etheno adduct repair.[Swenberg JA et al; IARC Sci Publ150: 29-43 (1999)]**PEER REVIEWED**Dose-response relationships of genotoxic agents differ greatly dependingon the agent & the endpoint being evaluated. Simple conclusions thatgenotoxic effects are linear cannot be applied universally. The shape ofthe molecular dose of DNA adducts varies from linear, to supralinear, tosublinear depending on metabolic activation & detoxication, &repair of individual types of DNA adducts. For mutagenesis and othergenotoxicity endpoints, the dose-response reflects the molecular dose ofeach type of DNA adduct, cell proliferation, as well as endogenous factorsthat lead to mutagenesis such as the formation & repair of endogenousDNA adducts. These same factors are important when interpreting the shapeof dose-response data for carcinogenesis of genotoxic agents, however,tumor background variability adds additional complexity. Endogenouslyformed DNA adducts may be identical to those formed by chemicals, as inthe case of vinyl chloride & ethylene oxide, or they may be thoseassociated with oxidative stress. Data presented in this paper demonstratethat the exogenous number of adducts induced by 5 days of exposure to 10ppm vinyl chloride is only 2.2-fold > that present as a steady-stateamount in unexposed control rats. Similar data are shown for ethyleneoxide. Extremely sensitive methods have been developed for measuring themolecular dose of genotoxins. These methods can detect DNA adducts as lowas 1 per 10(9) to 10(10). However, in view of the high number ofendogenous DNA adducts that are present in all cells, it is unlikely thatcausal relationships can be attributed to very low numbers of such DNAadducts. Effects of both exogenous & endogenous DNA adducts need to befactored into the interpretation of chemical exposures. [SWENBERG JA etal; MUTATION RESEARCH 464 (1): 77-86 (2000)]**PEER REVIEWED**Etheno adducts in DNA bases are formed from exogenous agents such as vinylchloride & urethane, but also via endogenous lipid peroxidationproducts like trans-4-hydroxy-2-nonenal. An immunohistochemical method was