MURINE LYMPHOCYTE SCE MODEL FOR PREDICTING GENOTOXIC RIS

外周血淋巴细胞姐妹染色单体互换分析 (PBLS)通常被用作人类遗传毒性暴露的指标 人口。这项提议的主要目标是检验这一假设： 未修复的姐妹染色单体互换诱发损伤的积聚及其持久性 在PBL中，由反复接触的化学物质产生，直接与 毒剂的致瘤活性。 由于人体研究的固有局限性，急性或慢性疾病的任何关联 人外周血中持续升高的SCES和危重患者的遗传毒性损伤 身体组织和/或致癌作用充其量只能推断。因此，作为一个 为了检验我们的假设，我们描述了一种平行示波图方法，该方法： 1.比较小鼠和人外周血淋巴细胞姐妹染色单体交换反应对一种已知致癌物的反应， L-苯丙氨酸芥末(L-PAM)，以及 2.比较小鼠外周血淋巴细胞姐妹染色单体交换反应与其他关键组织的反应 用不同致癌物质处理小鼠后 活动。 对于本研究的第一部分，使用L-PAM治疗的一个非常大的患者的姐妹染色单体交换 数据库可从当地研究中获得。这使我们能够设计 等量小鼠L-PAM治疗方案以确定是否 在治疗后姐妹染色单体交换反应中观察到相同的一般趋势 人和小鼠的外周血淋巴细胞。 在研究的第二部分，L-帕姆和其他人，如果时间允许， 烷化剂将用于使用已建立的肺的小鼠 腺瘤检测方案。SCES将在PBL、脾、淋巴中进行评估 不同时间间隔(24小时-15周)的结节和胸腺淋巴细胞 在最后一次治疗后。将讨论以下问题： 对所提出的动物模型的成功评估将提供基础 以备将来研究之用。例如，一种产生含糊不清的姐妹染色单体交换的化学品 在人类身上的结果可以在高剂量和低剂量下进行更全面的评估 动物模型，以确定人类的遗传毒性风险。此外, 新的化学物质可以在动物模型中进行评估，以便预测 在人类广泛接触之前，存在基因毒性风险。

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.