Temporal Concordance between Apical and Transcriptional Points-of-Departure for Chemical Risk Assessment

The number of legacy chemicals without toxicity reference values combined with the rate of new chemical development are overwhelming the capacity of the traditional risk assessment paradigm. More efficient approaches are needed to quantitatively estimate chemical risks. In this study, rats were dosed orally with multiple doses of six chemicals for 5 days, 2, 4, and 13 weeks. Target organs were analyzed for traditional histological and organ weight changes and transcriptional changes using microarrays. Histological and organ weight changes in this study and the tumor incidences in the original cancer bioassays were analyzed using benchmark dose (BMD) methods to identify noncancer and cancer points-of-departure. The dose-response changes in gene expression were also analyzed using BMD methods and the responses grouped based on signaling pathways. A comparison of transcriptional BMD values for the most sensitive pathway with BMD values for the noncancer and cancer apical endpoints showed a high degree of correlation at all time points. When the analysis included data from an earlier study with 8 additional chemicals, transcriptional BMD values for the most sensitive pathway were significantly correlated with noncancer (r = 0.827, p = 0.0031) and cancer-related (r = 0.940, p = 0.0002) BMD values at 13 weeks. The average ratio of apical-to-transcriptional BMD values was less than two suggesting that for the current chemicals, transcriptional perturbation did not occur at significantly lower doses than apical responses. Based on our results, we propose a practical framework for application of transcriptomic data to chemical risk assessment.缺乏毒性参考值的遗留化学品（legacy chemicals）数量，加之新化学品的研发速率，正远超传统风险评估范式的处理能力。亟需更高效的方法以定量评估化学品风险。本研究中，研究人员对大鼠经口给予6种化学品的多种剂量，染毒周期分别为5天、2周、4周及13周。针对靶器官，采用传统组织学、脏器重量检测方法结合微阵列（microarrays）技术分析其转录组变化。本研究中的组织学与脏器重量变化数据，以及原始癌症生物测定试验中的肿瘤发生率数据，均采用基准剂量（benchmark dose, BMD）方法进行分析，以确定非致癌与致癌效应的基准剂量起始点。基因表达的剂量响应变化同样采用BMD方法分析，并依据信号通路对响应结果进行分组。将最敏感通路的转录组BMD值，与非致癌及致癌顶端效应终点的BMD值进行对比，结果显示各时间点均存在高度相关性。当分析纳入此前一项包含8种额外化学品的研究数据后，在13周时间点，最敏感通路的转录组BMD值与非致癌（r = 0.827, p = 0.0031）及致癌相关（r = 0.940, p = 0.0002）BMD值仍存在显著相关性。顶端效应终点与转录组BMD值的平均比值小于2，表明对于本次研究涉及的化学品，转录组扰动并未显著低于顶端效应响应的发生剂量。基于本研究结果，我们提出了一套将转录组数据应用于化学品风险评估的实用框架。