Kasai Tatsuya, Kano Hirokazu, Umeda Yumi, Sasaki Toshiaki, Ikawa Naoki, Nishizawa Tomoshi, Nagano Kasuke, Arito Heihachiro, Nagashima Hiroshi, Fukushima Shoji
Japan Bioassay Research Center, Japan Industrial Safety and Health Association, Hadano, Kanagawa, Japan.
Inhal Toxicol. 2009 Sep;21(11):889-97. doi: 10.1080/08958370802629610.
Carcinogenicity and chronic toxicity of 1,4-dioxane were examined by inhalation exposure of 50 male F344 rats to 1,4-dioxane vapor at 0 (clean air), 50, 250, or 1250 ppm (v/v) for 6 h/day, 5 days/wk, and 104 wk. Survival rates of 250 and 1250 ppm-exposed groups were decreased near the end of the 2-yr exposure period, due probably to the occurrence of malignant tumors. A statistically significant but marginal decrement of terminal body weight (<10%) was found in the 1250 ppm-exposed group, suggesting slight systemic toxicity. Significant changes in plasma levels of AST, ALT, ALP, and gamma-GTP and relative weight of the liver occurred in the 1250 ppm-exposed group. Dose-dependent and statistically significant increases in incidences of nasal squamous cell carcinomas, hepatocellular adenomas, and peritoneal mesotheliomas were found primarily in the 1250 ppm-exposed group. The incidences of renal cell carcinomas, fibroadenomas in the mammary gland, and adenomas in the Zymbal gland were also increased dose-dependently. Preneoplastic lesions occurred in the nasal cavity and liver of the 1,4-dioxane-exposed groups. As nonneoplastic lesions, the significantly increased incidences of nuclear enlargement, atrophy, and respiratory metaplasia in the nasal cavity were noted at 50 ppm and above. A LOAEL (lowest observed adverse effect level) was determined at 50 ppm for the nasal endpoint of general chronic toxicity. This study provides clear evidence of carcinogenicity for 1,4-dioxane in male rats. A cytotoxic-proliferative and in vivo genotoxic mode of action is suggested to operate in 1,4-dioxane-induced carcinogenesis.
通过让50只雄性F344大鼠每天6小时、每周5天、共104周吸入浓度为0（清洁空气）、50、250或1250 ppm（体积/体积）的1,4 - 二氧六环蒸汽，研究了1,4 - 二氧六环的致癌性和慢性毒性。在2年暴露期接近结束时，暴露于250 ppm和1250 ppm组的存活率下降，这可能是由于恶性肿瘤的发生。在暴露于1250 ppm组中发现终末体重有统计学意义但幅度较小的下降（<10%），提示有轻微的全身毒性。暴露于1250 ppm组的血浆谷草转氨酶（AST）、谷丙转氨酶（ALT）、碱性磷酸酶（ALP）和γ-谷氨酰转肽酶（gamma - GTP）水平以及肝脏相对重量出现显著变化。主要在暴露于1250 ppm组中发现鼻鳞状细胞癌、肝细胞腺瘤和腹膜间皮瘤的发生率呈剂量依赖性且有统计学意义的增加。肾细胞癌、乳腺纤维腺瘤和鼓室腺腺瘤的发生率也呈剂量依赖性增加。在暴露于1,4 - 二氧六环的组的鼻腔和肝脏中出现了癌前病变。作为非肿瘤性病变，在50 ppm及以上浓度时，鼻腔中核肿大、萎缩和呼吸上皮化生的发生率显著增加。对于一般慢性毒性的鼻腔终点，最低观察到有害作用水平（LOAEL）确定为50 ppm。本研究提供了1,4 - 二氧六环对雄性大鼠具有致癌性的明确证据。提示细胞毒性 - 增殖和体内遗传毒性作用模式在1,4 - 二氧六环诱导的致癌过程中起作用。
