Genetic Toxicity Testing Services for the NTP

这份遗传毒理学测试合同支持了国家毒理学规划的总体任务，即在30年内提供有关化合物的详细毒理学概况，包括潜在致癌性。基因损伤的评估是癌症以及神经退行性疾病（如ALS）、神经系统疾病（如自闭症）、衰老、出生缺陷（如唐氏综合症）、线粒体疾病和其他对人类健康不利影响的病因学中的一个重要因素，是化学品或产品任何深入毒理学概况的关键组成部分。本遗传毒性检测合同提供了使用标准测试以及必要时创新协议的与NTP接触相关的遗传损害信息。合同的能力不断得到更新，以保持最新并符合进行这类试验的国际准则。所采用的检测系统包括体外（动物细胞和细菌）和体内（大鼠和小鼠）检测。还可以进行使用人体血液样本的体内研究，将动物研究的结果转化为人类接触情况。常规进行三种主要测试：体外细菌诱变性测试，体内啮齿动物外周血微核（MN）测试，以及体内啮齿动物多种组织（例如肝、脑、胃、肾和肺）的DNA损伤（Comet）测试。使用外周血作为样本来源，MN和Comet研究也可以在人类中进行。此外，体外MN测定法已越来越多地被用作独立的体内啮齿动物MN测定法的替代品。一个动物突变端点有望在未来的人类临床和生物监测研究中应用，已经在测试实验室进行了研究：猪- A突变试验（磷脂酰肌醇聚糖锚定生物合成，A类基因）。这种基因的突变很容易在实验室啮齿动物的红细胞样本中检测到，并且已经开发了简化分析的更新方法，因此可以很容易地将其整合到现有的毒性测试中。在未来的研究中，我们计划将该试验与体内MN和Comet试验相结合，增加我们从试验动物中获得的遗传损伤信息，以提供更全面的化学物质遗传毒性潜力资料。除了我们基于细胞和动物模型的研究外，NIOSH和NIEHS临床研究单位等合作者提供的人类血液样本也可以在疑似诱发遗传损伤的环境暴露后进行特定遗传终点的检查，或者在NTP动物研究中已经证明会这样做。上述每种类型的研究数量每年都有所不同，这取决于国家毒理学规划的需要。例如，在过去的一年里，国家毒理学计划遗传毒性测试实验室对14个升麻样本（植物产品）进行了创新性的体外染色体损伤研究，以提供机制信息，支持先前观察到的大鼠和小鼠MN诱导，并为国家毒理学计划目前正在使用该产品的妇女中进行的MN调查提供见解。这些测试是在每年计划的常规研究数量之外进行的。

This genetic toxicology testing contract has supported the overall mission of NTP to provide detailed toxicological profiles, including potential for carcinogenicity, of compounds of interest for 30 years. Assessment of genetic damage, an important factor in the etiology of cancer as well as neurodegenerative diseases such as ALS, neurological conditions such as autism, aging, birth defects such as Down syndrome, mitochondrial diseases, and other adverse human health effects, is a critical component of any in-depth toxicological profile of a chemical or product. This Genetic Toxicity Testing contract provides information on exposure-related genetic damage to NTP using standard tests as well as innovative protocols when necessary. The capabilities of the contract are continuously updated to remain current and compatible with international guidelines for conducting these kinds of tests. Testing systems employed include both in vitro (animal cell-based and bacterial) and in vivo (rats and mice) assays. In vivo studies using human blood samples can also be conducted to translate findings from animal studies to human exposure scenarios. Three main tests are conducted routinely: in vitro bacterial mutagenicity assays, in vivo rodent peripheral blood micronucleus (MN) assays, and in vivo rodent DNA damage (Comet) assays in multiple tissues including, for example, liver, brain, stomach, kidney, and lung. Using peripheral blood as the sample source, MN and Comet studies can also be conducted in humans. In addition, in vitro MN assays have become increasingly used as a substitute for stand-alone in vivo rodent MN assays. An animal mutation endpoint that holds promise for application in human clinical and biomonitoring studies in the future, has been investigated in the testing laboratory: the pig-a mutation assay (phosphatidylinositol glycan anchor biosynthesis, class A gene). Mutations in this gene are easily detected in red blood cell samples from laboratory rodents, and updated methods to streamline the assay have been developed, so that integration into existing toxicity tests can easily be accomplished. In future studies we plan to multiplex this assay with the in vivo MN and Comet assays, increasing the genetic damage information we obtain from test animals to provide an even more comprehensive profile of the genetic toxicity potential of a chemical. In addition to our cell-based and animal model studies, human blood samples provided by collaborators such as NIOSH and the NIEHS Clinical Research Unit may also be examined for specific genetic endpoints following an environmental exposure that is suspected of inducing genetic damage, or has been shown to do so in NTP animal studies. The number of studies of each type described above varies annually, depending on the needs of the NTP. For example, this past year, the NTP genetic toxicity testing laboratory conducted innovative in vitro chromosomal damage studies with 14 cohosh samples (botanical products) to provide mechanistic information to support the previously observed induction of MN in rats and mice, and to provide insight into the NTP’s MN investigations that are currently ongoing in women who are using this product. These tests were in addition to the usual number of studies planned annually.