Hailey James R, Nold James B, Brown Roger H, Cullen John M, Holder Julie C, Jordan Holly L, Ennulat Daniela, Miller Richard T
GlaxoSmithKline, Research Triangle Park, North Carolina, USA
WIL Research/Biotechnics, Hillsborough, North Carolina, USA.
Toxicol Pathol. 2014 Jul;42(5):844-54. doi: 10.1177/0192623313499976. Epub 2013 Aug 19.
Whether biliary proliferative lesions in nonclinical species are predictive of potential hepatotoxicity in humans depends, at least in part, on the nature and severity of such changes in the nonclinical species. We reviewed published literature (clinical and nonclinical) and experimental data from rat toxicology studies conducted by GlaxoSmithKline and the National Institute of Environmental Health Sciences' National Toxicology Program in an effort to better characterize the relative risk of hepatobiliary effects in humans. Available evidence supports the interpretation that minimal "typical" appearing bile duct hyperplasia limited to the portal triads may be considered non-adverse in the rat and is of little to no concern to humans. The toxicological relevance of mild to moderate "typical" hyperplasia is less certain, and may be considered adverse in the rat and potentially pose a risk for humans, particularly if accompanied by evidence of hepatobiliary injury or functional compromise. In addition, any proliferative lesion that includes atypical or dysplastic epithelial changes, oval cell proliferation, and/or significant extension beyond the portal tracts is considered more ominous and may be considered adverse in the rat.
非临床物种中的胆汁增生性病变是否能预测人类潜在的肝毒性，至少部分取决于非临床物种中此类变化的性质和严重程度。我们回顾了已发表的文献（临床和非临床）以及葛兰素史克公司和美国国立环境卫生科学研究所国家毒理学计划进行的大鼠毒理学研究的实验数据，以便更好地描述人类肝胆效应的相对风险。现有证据支持这样的解释：仅限于门三联的最小程度的“典型”胆管增生可能被认为对大鼠无不良影响，对人类几乎或没有影响。轻度至中度“典型”增生的毒理学相关性尚不确定，可能被认为对大鼠有不良影响，并可能对人类构成风险，特别是如果伴有肝胆损伤或功能损害的证据。此外，任何包括非典型或发育异常上皮变化、卵圆细胞增殖和/或超出门管区显著扩展的增生性病变被认为更不吉利，可能被认为对大鼠有不良影响。
