Shao Kan, Chen Qiran, Wang Zemin
Department of Environmental and Occupational Health, School of Public Health, Indiana University, Bloomington, IN, 47405, USA.
Toxicol Rep. 2019 Jul 8;6:674-682. doi: 10.1016/j.toxrep.2019.07.001. eCollection 2019.
Two-year toxicology and carcinogenesis rodent studies conducted at the National Toxicology Program (NTP) are used to identify potential adverse health effects in humans due to chemical exposure, including cancer. Liver tumor, the most frequently diagnosed tumor type of chemically induced neoplastic effects documented in NTP's carcinogenicity studies, is usually difficult to be detected at early stage due to the inconspicuous symptoms. However, the abnormal growth of liver cells can lead to liver weight increase, so it is hypothesized that liver tumor incidence is associated with early stage liver weight increase. In this study, the association between liver weight increase and liver tumor incidence are quantified by (1) calculating the correlation coefficient of and (2) building quantitative linear relationship between benchmark dose estimates derived from these two types of data collected from NTP studies. Together with 151 chemical/species/sex combinations of liver tumor data showing positive evidence collected from 76 NTP long-term studies, short-term liver weight data reported in the same NTP report were extracted to be paired with the liver tumor data for the analyses. Results show that the estimated correlation coefficients (as high as 0.78) along with the adequately fitted linear models suggest that the association between relative liver weight increase and aggregated liver tumor incidence are relatively strong. Additional analyses focused on some more specific situations (e.g., specific tumor type or specific strain/sex combination) further confirmed the strong association. Given the design of this study, the interpretation of the findings is not that liver weight increase can be used to predict liver tumor incidence, instead, evident increase in liver weight might be used as a reason to prioritize the test article for a two-year toxicology and carcinogenesis study.
美国国家毒理学计划（NTP）开展的为期两年的啮齿动物毒理学和致癌性研究，用于确定化学物质暴露对人类健康的潜在不良影响，包括致癌作用。肝肿瘤是NTP致癌性研究中记录的化学诱导肿瘤效应最常诊断出的肿瘤类型，由于症状不明显，通常很难在早期被检测到。然而，肝细胞的异常生长会导致肝脏重量增加，因此推测肝肿瘤发生率与早期肝脏重量增加有关。在本研究中，通过以下方式量化肝脏重量增加与肝肿瘤发生率之间的关联：（1）计算两者的相关系数；（2）根据从NTP研究收集的这两类数据得出的基准剂量估计值建立定量线性关系。从76项NTP长期研究中收集到的151种显示阳性证据的化学物质/物种/性别组合的肝肿瘤数据，与同一NTP报告中报告的短期肝脏重量数据进行配对，以提取用于分析。结果表明，估计的相关系数（高达0.78）以及拟合良好的线性模型表明，相对肝脏重量增加与汇总的肝肿瘤发生率之间的关联较强。针对一些更具体情况（如特定肿瘤类型或特定品系/性别组合）的进一步分析进一步证实了这种强关联。鉴于本研究的设计，研究结果的解释并非肝脏重量增加可用于预测肝肿瘤发生率，相反，肝脏重量的明显增加可能被用作优先对受试物进行两年毒理学和致癌性研究的一个理由。
