Twenty-six-Week carcinogenicity study of chloroform in CB6F1 rasH2-transgenic mice.
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 significant 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 nongenotoxic carcinogens. However, the sensitivity of rasH2-Tg mice to nongenotoxic carcinogens should be assessed with consideration of the results from the other ILSI-HESI project studies.
Sehata
Shinya
S
Medicinal Safety Research Laboratories, Sankyo Co, Ltd, Fukuroi, Shizuoka, Japan. sehata@fuku.sankyo.co.jp
Maejima
Takanori
T
Watanabe
Mayumi
M
Ogata
Seiya
S
Makino
Toshihiko
T
Tanaka
Kohji
K
Manabe
Sunao
S
Takaoka
Masaya
M
D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D030801:Animals, Genetically Modified; D015197:Carcinogenicity Tests; D002725:Chloroform / Q000633:toxicity*; D005260:Female; D011905:Genes, ras; D008297:Male; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D023421:Models, Animal; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D012997:Solvents / Q000633:toxicity*
D000477:Alkylating Agents; D012997:Solvents; D008770:Methylnitrosourea; D002725:Chloroform