NTP Database Summarization And Evaluation

该项目的目标是总结、评估和解释NTP啮齿动物致癌性数据库和其他大型数据库中包含的数据。最近的一项数据库评估显示，在过去的八年中，B6C3F1小鼠中自发性肝母细胞瘤的发病率增加了5倍。在此期间，产生肝母细胞瘤的化学物质数量也相应增加。特定的化学结构或生物学类别的化合物与其诱导肝母细胞瘤的能力之间没有明显的关联。 另一项数据库评估调查了来自35项最近NTP研究的1768只对照Fischer 344大鼠中背景前列腺、精囊和壶腹腺病变的特定肺叶发生率和严重程度。前列腺背外侧叶炎症与垂体腺瘤的发生密切相关，垂体腺瘤中的催乳素在前列腺炎症的发生中起重要作用。我们还发现，背外侧叶和腹侧叶组织的数量在实验室之间存在很大差异。我们推荐了一种最佳的大鼠前列腺和精囊的包埋和修剪方法，以确保足够和一致的采样。 博士Shyamal Peddada和我最近完成了经济合作与发展组织（OECD）子宫营养生物测定验证计划第二阶段的参与。该生物测定法旨在鉴定疑似雌激素激动剂或拮抗剂的化合物的体内活性，并帮助确定阳性化合物的优先顺序，以进行进一步检测。对未成年雌性大鼠和成年去卵巢大鼠两种模型系统进行了测试和比较。对来自十九个参与实验室的数据进行了评价，这些实验室使用七种不同的化学品，并采用了设盲和非设盲方案（每种方案均导致提交论文以供发表）。总体结论是，两种模型系统均表现出稳健性、可重复性和跨实验室可转移性，并且能够检测弱雌激素激动剂。

The goal of this project is to summarize, evaluate, and interpret data contained in the NTP rodent carcinogenicity database and other large databases. One recent database evaluation revealed a 5-fold increase in the incidence of spontaneous hepatoblastoma in B6C3F1 mice over the last eight years. There was also a corresponding increase in the number of chemicals producing hepatoblastoma during this time period. There was no apparent association between a specific chemical structure or biological class of compounds and their capacity to induce hepatoblastoma. Another database evaluation investigated the lobe-specific incidences and degrees of severity of background prostatic, seminal vesicular, and ampullary glandular lesions in 1768 control Fischer 344 rats from 35 recent NTP studies. Inflammation in the dorsolateral lobes of the prostate were significantly associated with the occurrence of pituitary gland adenoma, whose prolactin was suggested to play an important role in the pathogenesis of prostatic inflammation. We also found that the quantity of dorsolateral and ventral lobe tissue was highly variable across laboratories. We recommended an optimal embedment and trimming method in rat prostate and seminal vesicle to ensure adequate and consistent sampling. Dr. Shyamal Peddada and I recently completed our participation in the second phase of an Organization for Economic Co-operation and Development (OECD) validation program for the uterotrophic bioassay. This bioassay is intended to identify the in vivo activity of compounds that are suspected agonists or antagonists of estrogen, and to assist the prioritization of positive compounds for further testing. Two model systems, the immature female rat and the adult ovariectomized rat, were tested and compared. Data from nineteen participating laboratories using seven different chemicals, and both a blinded and unblinded protocol were evaluated (each leading to papers submitted for publication). The overall conclusions were that both model systems appear robust, reproducible and transferable across laboratories and able to detect weak estrogen agonists.