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Toxicologic Pathology
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Twenty-Six-Week Carcinogenicity Study of Chloroform in CB6F1 rasH2-Transgenic Mice

Shinya Sehata

Medicinal Safety Research Laboratories, Sankyo Co, Ltd, Fukuroi, Shizuoka 437-0065, Japan, sehata{at}fuku.sankyo.co.jp

Takanori Maejima

Medicinal Safety Research Laboratories, Sankyo Co, Ltd, Fukuroi, Shizuoka 437-0065, Japan

Mayumi Watanabe

Medicinal Safety Research Laboratories, Sankyo Co, Ltd, Fukuroi, Shizuoka 437-0065, Japan

Seiya Ogata

Medicinal Safety Research Laboratories, Sankyo Co, Ltd, Fukuroi, Shizuoka 437-0065, Japan

Toshihiko Makino

Medicinal Safety Research Laboratories, Sankyo Co, Ltd, Fukuroi, Shizuoka 437-0065, Japan

Kohji Tanaka

Medicinal Safety Research Laboratories, Sankyo Co, Ltd, Fukuroi, Shizuoka 437-0065, Japan

Sunao Manabe

Medicinal Safety Research Laboratories, Sankyo Co, Ltd, Fukuroi, Shizuoka 437-0065, Japan

Masaya Takaoka

Planning and Promotion Department, New Drug Development Division, Sankyo Co, Ltd, Chuo-ku, Tokyo 104-8133, Japan

The carcinogenic potential of chloroform was evaluated in a short-term carcinogenicity testing system using CB6F1 rasH2-Tg (rasH2-Tg) mice. Chloroform was administered to rasH2-Tg males at doses of 28, 90, or 140 mg/kg and rasH2-Tg females at 24, 90, or 240 mg/kg by oral gavage for 26 weeks. Wild-type (non-Tg) male and female mice received doses of 140 mg/kg and 240 mg/kg, respectively. N-methyl-N-nitrosourea was administered to rasH2-Tg mice by single intraperitoneal injection (75 mg/kg) as a positive control. In both the rasH2-Tg and non-Tg mice, there was no signifi cant increase in the incidence of neoplastic lesions by chloroform treatment. The incidence of hepatocellular foci in the rasH2- and non-Tg females receiving 240 mg/kg was increased. Forestomach tumors and malignant tumors occurred in most of the rasH2-mice in the positive control group. Swelling or vacuolation of hepatocytes, a toxic change induced by chloroform, occurred in both the rasH2-Tg and non-Tg mice. It is concluded that chloroform, a putative human noncarcinogen, did not show evidence of carcinogenic potential in the present study using rasH2-Tg mice. This study suggests that the rasH2-Tg mouse model may not be appropriate for detecting nongenotoxi c carcinogens. However, the sensitivity of rasH2-Tg mice to nongenotoxi c carcinogens should be assessed with consideration of the results from the other ILSI-HESI project studies.

Key Words: rasH2-Tg mouse • human prototype c-Ha-ras gene • short-term carcinogenicity testing • ILSI-HESI international collaborative project • N-methyl-N-nitrosourea.

Toxicologic Pathology, Vol. 30, No. 3, 328-338 (2002)
DOI: 10.1080/01926230252929909
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