Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine, University of Erlangen-Nuremberg, Henkestr. 9-11, 91054, Erlangen, Germany.
Environ Res. 2019 Jun;173:157-164. doi: 10.1016/j.envres.2019.03.025. Epub 2019 Mar 13.
It is still a major challenge to protect humans at workplaces and in the environment. To cope with this task, it is a prerequisite to obtain detailed information on the extent of chemical perturbations of biological pathways, in particular, adaptive vs. adverse effects and the dose-response relationships. This knowledge serves as the basis for the classification of non-carcinogens and carcinogens and for further distinguishing carcinogens in genotoxic (DNA damaging) or non-genotoxic compounds. Basing on quantitative dose-response relationships, points of departures can be derived for chemical risk assessment. In recent years, new methods have shown their capability to support the established rodent models of carcinogenicity testing. In vitro high throughput screening assays assess more comprehensively cell response. In addition, omics technologies were applied to study the mode of action of chemicals whereby the term "toxicogenomics" comprises various technologies such as transcriptomics, epigenomics, or metabolomics. This review aims to summarize the current state of toxicogenomic approaches in risk science and to compare them with established ones. For example, measurement of global transcriptional changes generates meaningful information for toxicological risk assessment such as accurate classification of genotoxic/non-genotoxic carcinogens. Alteration in mRNA expression offers previously unknown insights in the mode of action and enables the definition of key events. Based on these, benchmark doses can be calculated for the transition from an adaptive to an adverse state. In short, this review assesses the potential and challenges of transcriptomics and addresses the impact of other omics technologies on risk assessment in terms of hazard identification and dose-response assessment.
保护人类在工作场所和环境中的安全仍然是一个重大挑战。为了应对这一任务，首先需要详细了解生物途径的化学干扰程度，特别是适应性与不良反应以及剂量-反应关系。这些知识是对非致癌物和致癌物进行分类的基础，也是进一步区分遗传毒性（DNA 损伤）或非遗传毒性化合物中致癌物的基础。基于定量剂量-反应关系，可以得出化学风险评估的起始点。近年来，新方法已显示出支持已建立的致癌性测试啮齿动物模型的能力。体外高通量筛选试验更全面地评估细胞反应。此外，还应用了组学技术来研究化学物质的作用模式，其中“毒代动力学组学”包括转录组学、表观基因组学或代谢组学等各种技术。本文旨在总结毒代动力学方法在风险科学中的现状，并将其与已建立的方法进行比较。例如，测量全局转录变化为毒理学风险评估提供了有意义的信息，例如准确分类遗传毒性/非遗传毒性致癌物。mRNA 表达的改变为作用模式提供了以前未知的见解，并能够定义关键事件。在此基础上，可以计算从适应性到不良反应状态的转变的基准剂量。总之，本文评估了转录组学的潜力和挑战，并讨论了其他组学技术在危害识别和剂量-反应评估方面对风险评估的影响。
