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2
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从大鼠研究中的常见指标得出的阈值可预测肝脏致癌化学品。

Thresholds Derived From Common Measures in Rat Studies Are Predictive of Liver Tumorigenic Chemicals.

机构信息

Center for Computational Toxicology and Exposure, U.S. EPA, Research Triangle Park, NC, USA.

Department of Evolutionary Anthropology, 3065Duke University, Durham, NC, USA.

出版信息

Toxicol Pathol. 2020 Oct;48(7):857-874. doi: 10.1177/0192623320960412. Epub 2020 Oct 21.

DOI:10.1177/0192623320960412
PMID:33084515
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8610372/
Abstract

We hypothesized that typical tissue and clinical chemistry (ClinChem) end points measured in rat toxicity studies exhibit chemical-independent biological thresholds beyond which cancer occurs. Using the rat in vivo TG-GATES study, 75 chemicals were examined across chemical-dose-time comparisons that could be linked to liver tumor outcomes. Thresholds for liver weight to body weight (LW/BW) and 21 serum ClinChem end points were defined as the maximum and minimum values for those exposures that did not lead to liver tumors in rats. Upper thresholds were identified for LW/BW (117%), aspartate aminotransferase (195%), alanine aminotransferase (141%), alkaline phosphatase (152%), and total bilirubin (115%), and lower thresholds were identified for phospholipids (82%), relative albumin (93%), total cholesterol (82%), and total protein (94%). Thresholds derived from the TG-GATES data set were consistent across other acute and subchronic rat studies. A training set of ClinChem and LW/BW thresholds derived from a 38 chemical training set from TG-GATES was predictive of liver tumor outcomes for a test set of 37 independent TG-GATES chemicals (91%). The thresholds were most predictive when applied to 7d treatments (98%). These findings provide support that biological thresholds for common end points in rodent studies can be used to predict chemical tumorigenic potential.

摘要

我们假设，在大鼠毒性研究中测量的典型组织和临床化学（ClinChem）终点表现出超出癌症发生的化学独立的生物学阈值。使用大鼠体内 TG-GATES 研究，在可以与肝肿瘤结果相关联的化学剂量时间比较中检查了 75 种化学物质。肝重与体重比（LW/BW）和 21 种血清 ClinChem 终点的阈值被定义为那些不会导致大鼠肝肿瘤的暴露的最大和最小值。LW/BW（117%）、天门冬氨酸氨基转移酶（195%）、丙氨酸氨基转移酶（141%）、碱性磷酸酶（152%）和总胆红素（115%）的上限阈值被确定，而下限阈值被确定为磷脂（82%）、相对白蛋白（93%）、总胆固醇（82%）和总蛋白（94%）。从 TG-GATES 数据集得出的阈值在其他急性和亚慢性大鼠研究中是一致的。来自 TG-GATES 的 38 种化学物质的训练集的 ClinChem 和 LW/BW 阈值的训练集可预测 TG-GATES 的 37 种独立化学物质的测试集的肝肿瘤结果（91%）。当应用于 7d 处理时，这些阈值具有最高的预测性（98%）。这些发现支持在啮齿动物研究中常见终点的生物学阈值可用于预测化学致癌潜力。