A rat subchronic study transcriptional point of departure estimates a carcinogenicity study apical point of departure
A rat subchronic study transcriptional point of departure estimates a carcinogenicity study apical point of departure
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DOI：
10.1016/j.fct.2020.111869
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发表时间：
2021-01-01
影响因子：
4.3
通讯作者：
Johnson, Kamin J.
中科院分区：
文献类型：
--
作者：
Bianchi, Enrica;Costa, Eduardo;Johnson, Kamin J.
对人类相关性和动物使用的考虑正在推动研究，以确定为化学品风险评估提供信息的新方法，并取代基于准则的啮齿动物致癌性试验。在这里，对四种农用化学品的假设进行了测试：1)大鼠90天基于转录组的BEPOD对大鼠致癌性研究具有保护作用；2)亚慢性肝脏或肾脏BEPOD将近似于来自其他器官的癌症生物测定顶端POD，大鼠亚慢性BEPOD将近似于小鼠癌症生物测定顶端POD。使用RNA测序和bmexpress软件，在暴露于三氯吡啶酸、Pronamide、亚砜或芬吡嗪90天的雄性大鼠中产生肝脏和/或肾脏BEPOD值。将BEPOD值与从90天大鼠和啮齿动物致癌性研究中得出的基准剂量衍生的顶端POD值进行比较。在所有四种农用化学品中，研究结果表明，为期90天的大鼠研究BEPOD接近于90天大鼠研究和长期啮齿动物致癌性研究中产生的最敏感的顶端POD（在10倍之内）。该研究支持以下结论：基于亚慢性转录组的BEPOD可以在基于风险的农用化学品慢性毒性和致癌性评估方法中用于估计顶端POD，从而消除了对时间和资源密集的啮齿动物致癌性研究的需要，并最大限度地减少了动物试验。
Considerations of human relevance and animal use are driving research to identify new approaches to inform risk assessment of chemicals and replace guideline-based rodent carcinogenicity tests. Here, the hypothesis was tested across four agrochemicals that 1) a rat 90-day transcriptome-based BEPOD is protective of a rat carcinogenicity study and 2) a subchronic liver or kidney BEPOD would approximate a cancer bioassay apical POD derived from other organs and a rat subchronic BEPOD would approximate a mouse cancer bioassay apical POD. Using RNA sequencing and BMDExpress software, liver and/or kidney BEPOD values were generated in male rats exposed for 90 days to either Triclopyr Acid, Pronamide, Sulfoxaflor, or Fenpicoxamid. BEPOD values were compared to benchmark dose-derived apical POD values generated from rat 90-day and rodent carcinogenicity studies. Across all four agrochemicals, findings showed that a rat 90-day study BEPOD approximated the most sensitive apical POD (within 10-fold) generated from the 90-day rat study and long-term rodent carcinogenicity studies. This study supports the conclusion that a subchronic transcriptome-based BEPOD could be utilized to estimate an apical POD within a risk-based approach of chronic toxicity and carcinogenicity agrochemical assessment, abrogating the need for time- and resource-intensive rodent carcinogenicity studies and minimizing animal testing.