Carcinogenicity testing and the evaluation of regulatory requirements for pharmaceuticals
Carcinogenicity testing and the evaluation of regulatory requirements for pharmaceuticals
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DOI：
10.1006/rtph.1997.1085
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发表时间：
1997-04-01
影响因子：
3.4
通讯作者：
DeGeorge, JJ
中科院分区：
文献类型：
--
作者：
Contrera, JF;Jacobs, AC;DeGeorge, JJ
作为国际协调会议（ICH）评估啮齿动物致癌性研究及其在致癌性测试中的应用的一部分，FDA数据库中282种人类药物的大鼠和小鼠致癌性研究结果进行了分析和比较。FDA数据库中的大多数致癌性研究是在spraguedawley -derived大鼠和Swiss-Webster-derived CD-1小鼠中进行的，而不是在国家毒理学计划（NTP）研究中使用的Fisher 344大鼠和B6C3F1小鼠。尽管啮齿动物品系存在差异，但FDA数据库中阳性化合物的相对比例（44.3%）和大鼠与小鼠之间的总体一致性程度（74.1%）与NTP啮齿动物致癌性数据库相似。有必要对两种啮齿动物进行致癌性研究，主要是为了确定跨物种致瘤物质，这被认为比单一物种阳性化合物对人类构成相对更大的潜在风险。在大鼠和小鼠中进行的为期两年的致癌性研究可能并不是确定跨物种致癌物的唯一方法。目前已有足够的经验可用于一些替代的体内致癌性模型，以支持它们作为补充研究，与一项为期2年的单一致癌性研究相结合，以确定跨物种致癌性。我们对啮齿动物致癌性研究的分析支持这种评估致癌性潜力而不损害公众健康的方法。(C) 1997学术出版社。
The results of rat and mouse carcinogenicity studies for 282 human pharmaceuticals in the FDA database were analyzed and compared as part of an International Conference on Harmonization (ICH) evaluation of rodent carcinogenicity studies and their utility for carcinogenicity testing. A majority of the carcinogenicity studies in the FDA database were carried out in Sprague-Dawley-derived rats and Swiss-Webster-derived CD-1 mice in contrast to Fisher 344 rats and B6C3F1 mice employed in National Toxicology Program (NTP) studies. Despite the differences in rodent strains, the relative proportion of compounds with positive findings (44.3%) and the degree of overall concordance between rats and mice (74.1%) in the FDA database were similar to the NTP rodent carcinogenicity database. Carcinogenicity studies in two rodent species are necessary primarily to identify trans-species tumorigens, which are considered to pose a relatively greater potential risk to humans than single species positive compounds. Two-year carcinogenicity studies in both rats and mice may not be the only means of identifying transspecies tumorigens. Sufficient experience is now available for some alternative in vivo carcinogenicity models to support their application as complementary studies in combination with a single 2-year carcinogenicity study to identify trans-species tumorigens. Our analysis of the rodent carcinogenicity studies supports such an approach for assessing carcinogenic potential without compromising the public health. (C) 1997 Academic Press.