Genetic Toxicity Testing Services for the NTP

这份遗传毒理学测试合同支持了NTP的总体使命，即提供30年来感兴趣的化合物的详细毒理学概况，包括潜在的致癌能力。遗传损伤评估是癌症和神经退行性疾病(如肌萎缩侧索硬化症)、神经疾病(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重要因素，是任何深入的化学品或产品毒理学档案的关键组成部分。这份遗传毒性测试合同使用标准测试以及必要时的创新方案提供与接触NTP相关的遗传损害的信息。合同的能力不断更新，以保持最新情况，并与进行这类测试的国际准则相一致。采用的检测系统包括体外(基于动物细胞和细菌)和体内(大鼠和小鼠)检测。使用人类血液样本的活体研究也可以进行，以将动物研究的结果转化为人类暴露的情况。常规进行三项主要试验：体外细菌致突变试验、体内啮齿动物外周血微核试验(MN)和体内啮齿动物DNA损伤(彗星)试验，包括肝、脑、胃、肾和肺等多种组织。利用外周血作为样本来源，MN和彗星研究也可以在人类身上进行。此外，体外MN检测已经越来越多地被用来替代单独的啮齿动物体内MN检测。一种有望在未来应用于人类临床和生物监测研究的动物突变终点已经在测试实验室中进行了研究：PIG-A突变试验(磷脂酰肌醇葡聚糖锚定生物合成，A类基因)。在实验室啮齿动物的红细胞样本中很容易检测到这种基因的突变，并且已经开发出了简化检测的最新方法，这样就可以很容易地完成与现有毒性测试的整合。在未来的研究中，我们计划将这一分析与体内MN和彗星分析相结合，增加我们从实验动物中获得的遗传损伤信息，以提供一种化学物质遗传毒性潜力的更全面的概况。除了我们的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能在被怀疑会导致遗传损害的环境暴露后进行特定遗传终点的检查，或者在NTP动物研究中被证明是这样做的。上述每一类研究的数量每年都会有所不同，具体取决于NTP的需要。例如，在过去的一年里，NTP遗传毒性测试实验室对14个升麻样本(植物产品)进行了创新的体外染色体损伤研究，以提供机制信息来支持先前观察到的大鼠和小鼠MN的诱导，并深入了解NTP目前正在使用该产品的女性中进行的MN调查。这些测试是在每年计划的通常数量的研究之外进行的。

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.