Nonlinear Cancer Response at Ultralow Dose: A 40800-Animal ED001 Tumor and Biomarker Study
Nonlinear Cancer Response at Ultralow Dose: A 40800-Animal ED001 Tumor and Biomarker Study
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DOI：
10.1021/tx9000754
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发表时间：
2009-07-01
影响因子：
4.1
通讯作者：
Swenberg, James A.
中科院分区：
文献类型：
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作者：
Bailey, George S.;Reddy, Ashok P.;Swenberg, James A.
动物致癌物研究对人类癌症风险的评估受到严重限制，原因是与环境有关的接触实验数据不足，以及需要模拟外推的程序比可观察到的数据低许多数量级。我们使用虹鳟鱼（一种非常适合超低剂量致癌研究的动物模型）来探索剂量反应，直到每10000只动物中有10个多余的肝脏肿瘤（ED001）。总共40800只鳟鱼被喂食0-225 ppm二苯并[A， 1]芘（DBP） 4周，取样进行生物标志物分析，并返回对照组饮食9个月，然后进行大体和组织学检查。通过病理证实可疑肿瘤，并将由此产生的发病率建模，并与默认的EPA LED10线性外推方法进行比较。该研究提供了观察到的发生率数据，在最低剂量下，每10000只动物中有2只高于背景的肝脏肿瘤（即未建模的ED0002测量）。在探索的9个统计模型中，确定了3个很好地拟合肝脏数据-线性probit，二次logit和Ryzin-Rai。这些拟合模型都不符合LED10的默认假设，并且随着DBP剂量的降低，所有模型都越来越低于默认外推。肝脏DBP-DNA加合物生物标志物也无法预测低剂量肿瘤反应，其累积为剂量的幂函数（加合物= 100 x DBP1.31）。低于模型肿瘤数据的二阶外推预测DBP剂量每百万人（ED10-6）产生一个额外的癌症（ED10-6），比五阶LED10外推预测的高500-1500倍。这些结果被认为是特定于动物模型、致癌物和使用方案的。他们在任何保守程度的模型中提供了第一个实验估计，这种保守程度可能存在于EPA对遗传毒性致癌物的默认线性假设中。
Assessment of human cancer risk from animal carcinogen studies is severely limited by inadequate experimental data at environmentally relevant exposures and by procedures requiring modeled extrapolations many orders of magnitude below observable data. We used rainbow trout, an animal model wellsuited to ultralow-dose carcinogenesis research, to explore dose-response down to a targeted 10 excess liver tumors per 10000 animals (ED001). A total of 40800 trout were fed 0-225 ppm dibenzo[a,l]pyrene (DBP) for 4 weeks, sampled for biomarker analyses, and returned to control diet for 9 months prior to gross and histologic examination. Suspect tumors were confirmed by pathology, and resulting incidences were modeled and compared to the default EPA LED10 linear extrapolation method. The study provided observed incidence data down to two above-background liver tumors per 10000 animals at the lowest dose (that is, an unmodeled ED0002 measurement). Among nine statistical models explored, three were determined to fit the liver data well-linear probit, quadratic logit, and Ryzin-Rai. None of these fitted models is compatible with the LED10 default assumption, and all fell increasingly below the default extrapolation with decreasing DBP dose. Low-dose tumor response was also not predictable from hepatic DBP-DNA adduct biomarkers, which accumulated as a power function of dose (adducts = 100 x DBP1.31). Two-order extrapolations below the modeled tumor data predicted DBP doses producing one excess cancer per million individuals (ED10-6) that were 500-1500-fold higher than that predicted by the five-order LED10 extrapolation. These results are considered specific to the animal model, carcinogen, and protocol used. They provide the first experimental estimation in any model of the degree of conservatism that may exist for the EPA default linear assumption for a genotoxic carcinogen.