MURINE LYMPHOCYTE SCE MODEL FOR PREDICTING GENOTOXIC RIS

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Analysis of sister chromatid exchange (SCE) in peripheral blood lymphocytes (PBLs) is commonly used as an indicator of genotoxic exposures of human populations. The primary goal of this proposal is to test the hypothesis: The accumulation of unrepaired SCE-inducing lesions and their persistence in PBLs, produced by repeated chemical exposure, are directly related to the agent's tumorigenic activity. Due to inherent limitations of human studies any association of acute or persistently elevated SCEs in human PBL and genotoxic damage in critical body tissues and/or carcinogenesis is, at best, inferred. Therefore, as a means of testing our hypothesis we describe a parellelogram approach which: 1. Compares murine and human PBL SCE responses to a known carcinogen, L-phenylalanine mustard (L-PAM), and 2. Compares murine PBL SCE responses to responses in other critical tissues following treatment of mice with chemicals of varying carcinogenic activities. For the first part of this study a very large L-PAM-treated patient SCE data base is available from a local study. This enables us to design equivalent murine L-PAM treatment protocols in order to determine whether the same general post-treatment trends in SCE responses are observed in human and murine PBLs. In the second part of the study, L-PAM and, if time permits, other alkylating agents will be administered to mice using the established lung adenoma assay protocol. SCEs will be evaluated in PBLs, spleen, lymph node, and thymus lymphocytes at various time intervals (24 hrs - 15 wks) after the last treatment. The following questions will be addressed: Successful evaluation of the proposed animal model will provide the basis for future studies. For example, a chemical which produces ambiguous SCE results in humans can be more completely evaluated at high and low doses in the animal model in order to determine human genotoxic risk. In addition, new chemicals can be evaluated in the animal model in order to predict genotoxic risk prior to wide spread human exposure.