Integrating pathway-based transcriptomic data into quantitative chemical risk assessment: A five chemical case study
Integrating pathway-based transcriptomic data into quantitative chemical risk assessment: A five chemical case study
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DOI：
10.1016/j.mrgentox.2012.01.007
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发表时间：
2012-08-15
影响因子：
1.9
通讯作者：
Andersen, Melvin E.
中科院分区：
文献类型：
--
作者：
Thomas, Russell S.;Clewell, Harvey J., III;Andersen, Melvin E.
进行化学品风险评估的传统方法是时间和资源密集型的，导致作为人类健康决策依据的已公布的评估数量有限。相比之下，大多数受污染场地所含的化学品没有公布的参考值或癌症斜率系数，在计算总体危害指数时没有定量考虑这些因素。将转录组学技术纳入风险评估过程，可以提供一种有效的手段来定量评估与数据匮乏的化学品相关的健康风险。在之前的一项研究中，雌性B6 C3 F1小鼠暴露于多种浓度的五种化学物质，这些化学物质在为期两年的啮齿动物癌症生物测定中对肺和/或肝肿瘤形成呈阳性。将小鼠暴露13周，并使用微阵列分析靶组织的传统组织学和器官重量变化以及转录变化。在这项研究中，使用基准剂量（BMD）方法分析了基因表达的剂量反应变化，并根据途径对反应进行了分组。转录BMD值与传统非癌症和癌症顶端终点的比较显示特定途径的高度相关性。许多相关的途径已经涉及非癌症和癌症疾病的发病机制。结果表明，转录组学的变化，途径可用于估计非癌症和癌症的出发点，用于定量风险评估，并确定了潜在的毒性途径参与化学诱导的小鼠肺和肝脏的反应。(C)2012 Elsevier B. V.保留所有权利。
The traditional approach for performing a chemical risk assessment is time and resource intensive leading to a limited number of published assessments on which to base human health decisions. In comparison, most contaminated sites contain chemicals without published reference values or cancer slope factors that are not considered quantitatively in the overall hazard index calculation. The integration of transcriptomic technology into the risk assessment process may provide an efficient means to evaluate quantitatively the health risks associated with data poor chemicals. In a previous study, female B6C3F1 mice were exposed to multiple concentrations of five chemicals that were positive for lung and/or liver tumor formation in a two-year rodent cancer bioassay. The mice were exposed for a period of 13 weeks and the target tissues were analyzed for traditional histological and organ weight changes and transcriptional changes using microarrays. In this study, the dose-response changes in gene expression were analyzed using a benchmark dose (BMD) approach and the responses grouped based on pathways. A comparison of the transcriptional BMD values with those for the traditional non-cancer and cancer apical endpoints showed a high degree of correlation for specific pathways. Many of the correlated pathways have been implicated in non-cancer and cancer disease pathogenesis. The results demonstrate that transcriptomic changes in pathways can be used to estimate non-cancer and cancer points-of-departure for use in quantitative risk assessments and have identified potential toxicity pathways involved in chemically induced mouse lung and liver responses. (C) 2012 Elsevier B.V. All rights reserved.