Ultra-Low Dose Carcinogen Testing with the Trout Model

描述（由申请方提供）：外推动物剂量-反应致癌物数据以确定人类暴露的“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，保守的方法是假设线性。在啮齿动物模型中进行的最大肿瘤研究使用了24，192只小鼠，每100只小鼠中检测到1只癌症。鳟鱼肿瘤模型已被证明是有价值的，在确定致癌物质和它们的作用机制。鳟鱼对黄曲霉毒素B1（AFB 1）的肝癌性非常敏感，AFB 1是唯一通过食物供应暴露的IARC人类致癌物。肝细胞癌（HCC）每年在全球造成超过600，000例死亡，并且在某些地区占所有死亡的10-15%。肝癌是美国增长最快的实体瘤。对于AFB 1，鳟鱼和人类的靶器官、代谢、DNA内收和基因靶点相似，在本例中，鳟鱼模型上级小鼠。鳟鱼模型可以利用大量的动物来评估各种剂量的癌症。这种方法是可能的，因为这种模型的许多优点，包括自发性肿瘤发病率低和每日费用低。我们最近完成了在任何动物模型中最大的癌症研究，利用42，000条鳟鱼评估超低剂量二苯并[a，l]芘（DBP）的致癌性。该目标比小鼠ED 01研究低一个数量级，为1000分之一的癌症。我们的数据建立了一个剂量的DBP，导致1癌症在5,000鳟鱼和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AFB 1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，以检验第二种假设，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。

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.