SENSITIVE TRANSGENIC MODEL FOR CARCINOGEN DETECTION

在这一应用中，建议验证一种独特的转基因小鼠 遗传毒性致癌物鉴定模型。老鼠们已经被 基因工程过表达鸟氨酸脱羧酶(ODC) 皮肤和其他组织。结果，小鼠被内源性地“提升”了。 因此，对非常低的起始剂量的肿瘤诱导非常敏感 已知的皮肤致癌物质。该模型将通过以下方式进一步验证 对几种致癌物质进行剂量反应研究 非致癌化合物。上呼吸道消化的敏感性 已知致癌物的轨迹也将在此模型中进行评估。这个 这一应用中的技术创新潜力是 可能，第一次，一个短期的，高度敏感的和 廉价的体内模型将可用于测试可疑化学物质 低剂量，与典型的人类暴露更相关，而不是最大剂量 目前测试系统中普遍采用的耐受剂量。就.而言 化学风险评估，使用这一结果是可行的 以低剂量数据为基础的监管决策模型，而不是必须 按照目前的做法，从高剂量数据进行外推。 建议的商业应用 将开发一种体内模型来测试致癌潜力 药物、环境化学品和饮食成分。因为 模型非常敏感，化学物质可以在低剂量下进行测试， 与人类接触水平相当。

In this application, it is proposed to validate a unique transgenic mouse model for identification of genotoxic carcinogens. The mice have been engineered to overexpress the enzyme ornithine decarboxylase (ODC) in skin and other tissues. As a result, the mice are endogenously "promoted" and thus very sensitive for tumor induction to very low, initiating doses of known skin carcinogens. The model will be further validated by conducting dose-response studies for several carcinogenic and noncarcinogenic compounds. The sensitivity of the upper aerodigestive tract to a known carcinogen will also be evaluated in this model. The potential for technological innovation in this application is the likelihood that, for the first time, a short-term, highly sensitive and inexpensive in vivo model will be available to test suspect chemicals at low doses, more relevant to typical human exposures than the maximum tolerated doses commonly employed in current test systems. In terms of chemical risk assessment, it could be feasible using results from this model to base regulatory decisions on low dose data, rather than have to extrapolate from high dose data as is currently done. PROPOSED COMMERCIAL APPLICATIONS An in vivo model will be developed for testing the carcinogenic potential of drugs, environmental chemicals, and dietary constituents. Because the model is extremely sensitive, chemicals can be tested at low doses, comparable to human exposure levels.