SOURCES OF VARIABILITY IN TUMOR INCIDENCE IN LONG TERM RODENT STUDIES

利用3-染色体荧光原位杂交技术（FISH）建立了小鼠附睾精子非整倍体（梅萨）检测方法，用于评价化学物质对雄性生殖细胞的非整倍性作用。我们调查了影响评分员间和实验室间反应变异性的因素。我们确定显微镜评分标准为实验室间变异的主要来源，这强调了严格的技术控制的重要性。我们的研究结果表明，观察到的评分员、样本和治疗组之间的两个差异因素目前在梅萨测定的正常变化范围内，在没有独立确认的情况下，应谨慎看待这种幅度的差异。在过去的一年中，我们还完成了统计模型的开发，以考虑Tg.AC小鼠生物测定中皮肤乳头状瘤发生率和多样性的动物间和时间相关变异性。另一项研究是在对照雄性Fischer 344大鼠中调查肾小管细胞腺瘤与慢性进行性肾病（CPN）严重程度之间的关联。 初步结果表明，大鼠与更严重的CPN有轻微增加的风险，发展肾小管腺瘤相对于同等年龄的动物与较低的CPN的严重程度。

The mouse epididymal sperm anueploidy (mESA) assay using 3-chromosome fluorescence in situ hybridization (FISH) was recently developed for assessing the aneugenic potential of chemicals on male germ cells. We investigated the factors affecting inter-scorer and inter-laboratory variability in response. We identified microscope scoring criteria as the major source of interlaboratory variation, which emphasizes the importance of strict technical controls for the assay. Our findings suggest that observed factors of two differences between scorers, samples, and treatment groups are currently within the normal variation of the mESA assay, and differences of this magnitude should be viewed with caution without independent confirmation. During the past year, we also completed the development of statistical models to take into account animal-to-animal and time-related variability in the incidence and multiplicity of skin papilloma in Tg.AC mouse bioassays. Another study is investigating the association between renal tubule cell adenoma and the severity of chronic progressive nephropathy (CPN) in control male Fischer 344 rats. Preliminary results suggest that rats with more severe CPN have a slightly increased risk of developing kidney tubular adenoma relative to equivalently-aged animals with lesser CPN severity.