A MODEL FOR PERSISTENCE OF SCE LESIONS

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Our recently developed path analysis model for evaluation of SCE's induced by alkylating agents makes predictions regarding expected SCE frequencies in terms of the total number of lesions induced, the probability of a lesion inducing an SCE, and the extent of repair over successive cell cycles following treatment with alkylating agents. Our model which, incorporates enumeration of SCE frequencies in second and third division progeny of cells exposed at various cell cycle intervals relative to BrdU incorporation, is particularly useful for assessing either persistence or repair of SCE inducing lesions. The major aim of the present proposal is to further evaluate our model by examining SCE's induced in vivo by standard alkylating agents whose spectra of DNA alkylation sites and rates of repair are well characterized. Specific aims in this study include: 1) ascertainment of the nature of specific SCE inducing lesions and their associated SCE inducing efficiencies; 2) identification of tissue susceptibilities (bone marrow, alveolar macrophage, and liver) to specific agents; 3) evaluation of either persistence or repair of SCE inducing lesions in critical times over successive post-treatment cell cycle initervals; and 4) evaluation of induced cytotoxicity by examination of (a) a shift in distribution of percentages of first, second, and third division cells (b) lack of agreement of second division SCE's and nonreciprocal SCE frequencies in their third division progeny. The standard alkylating agents to be employed include: methyl methanesulfonate, ethyl methanesulfonate, dimethyl nitrosamine, diethylnitrosamine, methyl nitrosourea and ethyl nitrosourea. Direct acting Beta-chloroethylnitrosourea will be employed as a model direct-acting cross-linking agent and vinyl carbamate, a suspected metabolite of ethyl carbamate and a potential model for vinyl chloride will be examined regarding its ability to form cross-links analogous to those produced by Beta-chloroethylnitrosourea.