Hard G C, Boorman G A, Wolf D C
American Health Foundation, Valhalla, New York 10595, USA.
Toxicol Sci. 2000 Feb;53(2):237-44. doi: 10.1093/toxsci/53.2.237.
Chloroform, generally regarded as a non-genotoxic compound, is associated with the induction of liver and/or kidney tumors in laboratory mice and rats. In particular, chloroform produced renal tubule tumors in low incidence in male Osborne-Mendel rats when administered by corn-oil gavage or in the drinking water. There is a lack of data on intermediate endpoints that may be linked to renal cancer development in this strain of rat, in contrast to mice. Specifically, evidence linking chloroform-induced liver and kidney tumors in mice with cytotoxicity and regenerative cell proliferation is very strong, but weak in the rat. In the present study, kidney tissue from a carcinogenicity bioassay of chloroform in Osborne-Mendel rats was re-evaluated for histological evidence of compound-induced cytotoxicity and cell turnover. All rats treated with 1800 ppm (160 mg/kg/day, high-dose group) in the drinking water for 2 years and half the rats treated with 900 ppm (81 mg/kg/day) had mild to moderate changes in proximal convoluted tubules in the mid to deep cortex indicative of chronic cytotoxicity. Tubule alterations specifically associated with chronic chloroform exposure included cytoplasmic basophilia, cytoplasmic vacuolation, and nuclear crowding consistent with simple tubule hyperplasia. Occasional pyknotic cells, mitotic figures in proximal tubules, and prominent karyomegaly of the renal tubule epithelium were present. These alterations were not present in control groups or at the 200-ppm (19 mg/kg/day) or 400-ppm (38 mg/kg/day) dose levels. This new information adds substantially to the weight of evidence that the key events in chloroform-induced carcinogenicity in rat kidney include sustained cellular toxicity and chronic regenerative hyperplasia.
氯仿一般被认为是一种非遗传毒性化合物，但在实验室小鼠和大鼠中会诱发肝脏和/或肾脏肿瘤。特别是，当通过玉米油灌胃或饮水给予氯仿时，雄性奥斯本-孟德尔大鼠中会以低发病率产生肾小管肿瘤。与小鼠相比，缺乏关于可能与该品系大鼠肾癌发生相关的中间终点数据。具体而言，将氯仿诱导的小鼠肝脏和肾脏肿瘤与细胞毒性和再生细胞增殖联系起来的证据非常充分，但在大鼠中则较弱。在本研究中，对氯仿在奥斯本-孟德尔大鼠致癌性生物测定中的肾脏组织进行了重新评估，以寻找化合物诱导的细胞毒性和细胞更新的组织学证据。所有在饮水中接受1800 ppm（160 mg/kg/天，高剂量组）处理2年的大鼠以及一半接受900 ppm（8l mg/kg/天）处理的大鼠，在中深层皮质的近端曲管中有轻度至中度变化，表明存在慢性细胞毒性。与慢性氯仿暴露特别相关的肾小管改变包括细胞质嗜碱性、细胞质空泡化以及与单纯肾小管增生一致的核拥挤。近端小管中偶尔出现固缩细胞、有丝分裂象以及肾小管上皮细胞核显著肿大。对照组或200 ppm（19 mg/kg/天）或400 ppm（38 mg/kg/天）剂量组中未出现这些改变。这一新信息大大增加了证据权重，表明氯仿诱导大鼠肾脏致癌性的关键事件包括持续的细胞毒性和慢性再生性增生。
