Waters Michael D, Selkirk James K, Olden Kenneth
National Center for Toxicogenomics, 111 Alexander Drive, P.O. Box 12233, MD F1-05, Research Triangle Park, NC 27709-2233, USA.
Mutat Res. 2003 Nov;544(2-3):349-60. doi: 10.1016/j.mrrev.2003.06.022.
Human population studies involve clinical or epidemiological observations that associate environmental exposures with health endpoints and disease. Clearly, these are the most sought after data to support assessments of human health risk from environmental exposures. However, the foundations of many health risk assessments rest on experimental studies in rodents performed at high doses that elicit adverse outcomes, such as organ toxicity or tumors. Using the results of human studies and animal data, risk assessors define the levels of environmental exposures that may lead to disease in a portion of the population. These decisions on potential health risks are frequently based on the use of default assumptions that reflect limitations in our scientific knowledge. An important immediate goal of toxicogenomics, including proteomics and metabonomics, is to offer the possibility of making decisions affecting public health and public based on detailed toxicity, mechanistic, and exposure data in which many of the uncertainties have been eliminated. Ultimately, these global technologies will dramatically impact the practice of public health and risk assessment as applied to environmental health protection. The impact is already being felt in the practice of toxicology where animal experimentation using highly controlled dose-time parameters is possible. It is also being seen in human population studies where understanding human genetic variation and genomic reactions to specific environmental exposures is enhancing our ability to uncover the causes of variations in human response to environmental exposures. These new disciplines hold the promise of reducing the costs and time lines associated with animal and human studies designed to assess both the toxicity of environmental pollutants and efficacy of therapeutic drugs. However, as with any new science, experience must be gained before the promise can be fulfilled. Given the numbers and diversity of drugs, chemicals and environmental agents; the various species in which they are studied and the time and dose factors that are critical to the induction of beneficial and adverse effects, it is only through the development of a profound knowledge base that toxicology and environmental health can rapidly advance. The National Institute of Environmental Health Sciences (NIEHS), National Center for Toxicogenomics and its university-based Toxicogenomics Research Consortium (TRC), and resource contracts, are engaged in the development, application and standardization of the science upon which to the build such a knowledge base on Chemical Effects in Biological Systems (CEBS). In addition, the NIEHS Environmental Genome Project (EGP) is working to systematically identify and characterize common sequence polymorphisms in many genes with suspected roles in determining chemical sensitivity. The rationale of the EGP is that certain genes have a greater than average influence over human susceptibility to environmental agents. If we identify and characterize the polymorphism in those genes, we will increase our understanding of human disease susceptibility. This knowledge can be used to protect susceptible individuals from disease and to reduce adverse exposure and environmentally induced disease.
人群研究涉及临床或流行病学观察，将环境暴露与健康终点和疾病联系起来。显然，这些是支持评估环境暴露对人类健康风险最受追捧的数据。然而，许多健康风险评估的基础是在啮齿动物身上进行的高剂量实验研究，这些研究引发了不良后果，如器官毒性或肿瘤。风险评估人员利用人体研究结果和动物数据，确定可能导致部分人群患病的环境暴露水平。这些关于潜在健康风险的决策通常基于一些默认假设，这些假设反映了我们科学知识的局限性。包括蛋白质组学和代谢组学在内的毒理基因组学的一个重要近期目标是，提供基于详细的毒性、作用机制和暴露数据做出影响公众健康和公共决策的可能性，其中许多不确定性已被消除。最终，这些全球性技术将极大地影响应用于环境卫生保护的公共卫生实践和风险评估。这种影响已经在毒理学实践中显现出来，在毒理学中，可以使用高度可控的剂量-时间参数进行动物实验。在人群研究中也可以看到这种影响，了解人类基因变异以及基因组对特定环境暴露的反应正在增强我们揭示人类对环境暴露反应差异原因的能力。这些新学科有望降低与旨在评估环境污染物毒性和治疗药物疗效的动物和人体研究相关的成本和时间线。然而，与任何新科学一样，在实现这一前景之前必须积累经验。考虑到药物、化学品和环境因子的数量和多样性；研究它们的各种物种以及对产生有益和不良影响至关重要的时间和剂量因素，只有通过建立深厚的知识库，毒理学和环境卫生才能迅速发展。美国国立环境卫生科学研究所（NIEHS）、国家毒理基因组学中心及其基于大学的毒理基因组学研究联盟（TRC）以及资源合同，都在致力于开展、应用和标准化相关科学，以建立这样一个关于生物系统化学效应（CEBS）的知识库。此外，NIEHS环境基因组计划（EGP）正在努力系统地识别和表征许多怀疑在决定化学敏感性方面起作用的基因中的常见序列多态性。EGP的基本原理是某些基因对人类对环境因子的易感性影响大于平均水平。如果我们识别并表征这些基因中的多态性，我们将增进对人类疾病易感性的理解。这些知识可用于保护易感个体免受疾病侵害，并减少不良暴露和环境诱发疾病。
