Application of Transcriptional Benchmark Dose Values in Quantitative Cancer and Noncancer Risk Assessment
Application of Transcriptional Benchmark Dose Values in Quantitative Cancer and Noncancer Risk Assessment
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DOI：
10.1093/toxsci/kfq355
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发表时间：
2011-03-01
影响因子：
3.8
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.
在定量化学品风险评估中，传统的评估非致癌参考值和致癌参考值的方法耗费大量时间和资源。传统方法所要求的研究的范围和性质限制了已发表风险评估的化学品的数量。在这项研究中，雌性小鼠在13周内暴露于5种化学物质的多种浓度中，这些化学物质在2年的癌症生物测定中呈阳性。评估传统组织学和器官重量变化，并对靶组织进行基因表达微阵列分析。使用标准基准剂量（BMD）方法分别分析原始癌症生物测定中的组织学、器官重量变化和原始肿瘤发生率，以确定非癌症和癌症的出发点。使用BMD方法分析了基因表达的剂量相关变化，并根据细胞生物学过程对反应进行了分组。将转录BMD值与传统的非癌症和癌症顶点端点的转录BMD值进行比较，显示出特定细胞生物学过程的高度相关性。对于具有人体暴露数据的化学品，转录BMD值也用于计算暴露边际。暴露的边缘在1900到54,000之间。转录终点和根尖终点骨密度值之间的相关性以及暴露边缘分析表明，转录终点骨密度值可作为非癌症和癌症风险评估的潜在起点。
The traditional approach for estimating noncancer and cancer reference values in quantitative chemical risk assessment is time and resource intensive. The extent and nature of the studies required under the traditional approach has limited the number of chemicals with published risk assessments. In this study, female mice were exposed for 13 weeks to multiple concentrations of five chemicals that were positive in a 2-year cancer bioassay. Traditional histological and organ weight changes were evaluated, and gene expression microarray analysis was performed on the target tissues. The histological, organ weight changes, and the original tumor incidences in the original cancer bioassay were analyzed using standard benchmark dose (BMD) methods to identify noncancer and cancer points of departure, respectively. The dose-related changes in gene expression were also analyzed using a BMD approach and the responses grouped based on cellular biological processes. A comparison of the transcriptional BMD values with those for the traditional noncancer and cancer apical endpoints showed a high degree of correlation for specific cellular biological processes. For chemicals with human exposure data, the transcriptional BMD values were also used to calculate a margin of exposure. The margins of exposure ranged from 1900 to 54,000. Both the correlation between the BMD values for the transcriptional and apical endpoints and the margin of exposure analysis suggest that transcriptional BMD values may be used as potential points of departure for noncancer and cancer risk assessment.