Ultra-Low Dose Carcinogen Testing with the Trout Model

使用鳟鱼模型进行超低剂量致癌物测试

• 批准号: 7256364
• 负责人: David E Williams
• 金额: $ 49.36万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256364
• 关键词: 2-Acetylaminofluorene; Accounting; Address; Aflatoxin B1; Aflatoxins; Animal Model; Animals; Apoptosis; Biological Markers; Bladder; Carcinogen exposure; Carcinogenicity Tests; Carcinogens; Cell Proliferation; Cessation of life; Coupled; Custom; DNA Adduction; Data; Dibenzo (a,l) pyrene; Disease; Dose; Environmental Carcinogens; Exhibits; Female; Food Supply; Gene Expression; Gene Targeting; Housing; Human; Inbred BALB C Mice; Incidence; International Agency for Research on Cancer; Linear Models; Literature; Liver; Liver neoplasms; Malignant Neoplasms; Measurement; Measures; Metabolism; Methods; Modeling; Molecular; Mus; Numbers; Oncogene Activation; Oncorhynchus mykiss; Oregon; Organ; Pathology; Primary carcinoma of the liver cells; Process; Protocols documentation; Pyrenes; Range; Research Personnel; Risk Assessment; Rodent; Rodent Model; Salmo trutta; Sampling; Solid Neoplasm; Study models; Testing; Time; United States Environmental Protection Agency; Universities; animal data; cancer chemoprevention; cancer risk; carcinogenesis; carcinogenicity; cost; dosimetry; exposed human population; programs; pyrene; response; tumor

DESCRIPTION (provided by applicant): Extrapolation of dose-response carcinogen data from animals to establish "safe" levels for human exposures (1 in a million) is challenging as it requires modeling of dose-response over at least 4 orders of magnitude. In many cases, the conservative approach is assumed linearity. The largest tumor study in a rodent model used 24,192 mice to detect 1 cancer in 100. The trout tumor model has proven valuable in identification of carcinogens and their mechanism of action. Trout are very sensitive to the hepatocarcinogenicity of aflatoxin B1 (AFB1), the only IARC human carcinogen where exposure is through the food supply. Hepatocellular carcinoma (HCC) is responsible for over 600,000 deaths a year worldwide and accounts for 10-15% of all deaths in certain regions. HCC is the most rapidly increasing solid tumor in the U.S. For AFB1, the target organ, metabolism, DNA adduction and gene targets are similar in trout and human and, in this example, the trout model is superior to mouse. The trout model can utilize large numbers of animals to evaluate cancer across a wide range of doses. This approach is possible due to a number of advantages of this model including low spontaneous tumor incidence and low per diem costs. We have recently completed the largest cancer study in any animal model, utilizing 42,000 trout to assess carcinogenicity of dibenzo[a,l]pyrene (DBP) at ultra-low doses. The target was an order of magnitude lower than the mouse ED01 study, to one cancer in 1000. Our data established a dose of DBP that resulted in 1 cancer in 5,000 trout and the dose-response was non-linear. We now propose to utilize this ultra-low dose model to test the hypothesis that the non-linearity of cancer incidence at ultra-low dose also applies to AFB1. Tumor incidence data will be coupled with measurements of molecular dosimetry, cell proliferation, apoptosis and gene expression utilizing a custom microarray in order to test the second hypothesis, that in contrast to tumor incidence, these biomarkers of carcinogenicity exhibit linearity across the entire tumor dose-response range.

描述（由申请人提供）：根据动物的剂量反应致癌物数据外推来确定人类暴露的“安全”水平（百万分之一）具有挑战性，因为它需要对至少 4 个数量级的剂量反应进行建模。在许多情况下，保守方法假设是线性的。最大的啮齿动物模型肿瘤研究使用了 24,192 只小鼠，检测出 100 只小鼠中的 1 种癌症。事实证明，鳟鱼肿瘤模型在鉴定致癌物及其作用机制方面具有重要价值。鳟鱼对黄曲霉毒素 B1 (AFB1) 的肝癌致癌性非常敏感，黄曲霉毒素 B1 是唯一通过食品供应接触的 IARC 人类致癌物。肝细胞癌 (HCC) 每年导致全球超过 600,000 人死亡，占某些地区所有死亡人数的 10-15%。 HCC 是美国增长最快的实体瘤。对于 AFB1，鳟鱼和人类的靶器官、代谢、DNA 加成和基因靶标相似，在本例中，鳟鱼模型优于小鼠。鳟鱼模型可以利用大量动物来评估各种剂量下的癌症。这种方法之所以可行，是因为该模型有许多优点，包括自发性肿瘤发生率低和每日成本低。我们最近完成了最大的动物模型癌症研究，利用 42,000 条鳟鱼来评估超低剂量的二苯并[a,l]芘 (DBP) 的致癌性。该目标比小鼠 ED01 研究低一个数量级，为 1000 条鳟鱼中 1 例患癌症。我们的数据确定了 DBP 剂量，该剂量导致 5,000 条鳟鱼中 1 例患癌症，并且剂量反应是非线性的。我们现在建议利用这种超低剂量模型来检验超低剂量下癌症发病率的非线性也适用于 AFB1 的假设。肿瘤发生率数据将与使用定制微阵列的分子剂量测定、细胞增殖、细胞凋亡和基因表达的测量相结合，以检验第二个假设，即与肿瘤发生率相反，这些致癌性生物标志物在整个肿瘤剂量反应范围内表现出线性。