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

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.

References

• Ando K., Saitoh A., Hino O., Takahashi R., Kimura M., Katsuki M. (1992). Chemically induced forestomach papillomas in transgenic mice carrying mutant human c-Ha-ras oncogenes. Cancer Res 52: 978—982.[Abstract/Free Full Text]
• Boorman GA, Maronpot RR, Eustis SL (1994). Rodent carcinogenicity bioassay: Past, present, and future. Toxicol Pathol 22: 105—111.[Abstract/Free Full Text]
• Bos JL (1989). Ras oncogenes in human cancer: A review. Cancer Res 49: 4682—4689.[Abstract/Free Full Text]
• Butterworth BE, Conolly RB, Morgan KT (1995). A strategy for establishing mode of action of chemical carcinogens as a guide for approaches to risk assessments. Cancer Lett 93: 129—146.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Constan AA, Sprankle CS, Peters JM, Kedderis GL, Everitt JI, Wong BA, Gonzalez FL, Butterworth BE (1999). Metabolism of chloroform by cytochrome P4502E1 is required for induction of toxicity in the liver, kidney, and nose of male mice. Toxicol Appl Pharmacol 160: 120—126.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Danielsson BRG, Ghantous H., Dencker L. (1986). Distribution of chloroform and methyl chloroform and their metabolites in pregnant mice. Biol Res Pregnancy 7:77—83.
• Davis TS, Monro A. (1995). Marked human pharmaceuticals reported to be tumorigenic in rodents. J Am Coll Toxicol 14: 90—107.[Web of Science]
• Doyle TJ, Zheng W., Cerhan JR, Hong CP, Sellers TA, Kushi LH, Folsom AR (1997). The association of drinking water source and chlorination byproducts with cancer incidence among postmenopausal women in Iowa: A prospective cohort study. Am J Public Health 87: 1168—1176.[Abstract/Free Full Text]
• Guerroro I., Pellicer A. (1987). Mutational activation of oncogenes in animal model systems of carcinogenesis. Mutat Res 185: 293—308.[Web of Science][Medline] [Order article via Infotrieve]
• Gulezian D., Jacobson-Kram D., McCullough CB, Olson H., Recio L., Robinson D., Storer R., Tennant R., Ward JM, Neumann DA (2000). Use of transgenic animals for carcinogenicity testing: Considerations and implications for risk assessment. Toxicol Pathol 28: 482—499.[Abstract/Free Full Text]
• Hard GC, Boorman GA, Wolf DC ( 2000). Re-evaluation of the 2-year chloroform drinking water carcinogenicity bioassay in Osborne—Mendel rats supports chronic renal tubule injury as the mode of action underlying the renal tumor response. Toxicol Sci 53: 237—244.[Abstract/Free Full Text]
• Hoff G., Moen IE, Mowinckel P., Rosef O, Nordbö, Sauar J., Vatn MH, Torgrimsen T. (1992). Drinking water and the prevalence of colorectal adenomas: An epidemiologic study in Telemark, Norway. Eur J Cancer Prev 1:423—428.[Medline] [Order article via Infotrieve]
• International Agency for Research on Cancer ( 1978). N-nitroso-Nmethylurea. In: IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Vol. 17, Some N-Nitroso Compounds. International Agency for Research on Cancer, Lyon, France, pp 227— 255.
• International Conference on Harmonization (1997). ICH Harmonized Tripartite Guideline: Testing for carcinogenicity of pharmaceuticals, Step 4.
• Jergenson TA, Meierhenry EF, Rushbook CJ, Bull RJ, Robinson M. (1985). Carcinogenicity of chloroform in drinking water to male Osborne— Mendel rats and female B6C3F1 mice. Fundam Appl Toxicol 5: 760— 769.
• Katsutani N., Sekido T., Aoki T., Sagami F. (2000). Hepatic drug metabolizing enzymes induced by clofibrate in rasH2 mice. Toxicol Lett 115: 223—229.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Larson JL, Templin MV, Wolf DC, Jamison KC, Leininger JR, Mery S., Morgan KT, Wong BA, Conolly RB, Butterworth BE (1996). A 90-day chloroform inhalation study in female and male B6C3F1 mice: Implications for cancer risk assessment. Fundam Appl Toxicol 30: 118— 137.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Larson JL, Wolf DC, Butterworth BE (1994). Induced cytotoxicity and cell proliferation in the hepatotoxicity of chloroform in female B6C3F1 mice: Comparison of administration by gavage in corn oil vs. ad libitum in drinking water. Fundam Appl Toxicol 22: 90—102.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Mery S., Larson JL, Burrerworth BE, Wolf DC, Harden R., Morgan KT (1994). Nasal toxicity of chloroform in male F-344 rats and female B6C3F1 micefollowing a 1-week inhalation exposure. Toxicol Appl Pharmacol 125: 214—227.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Mitsumori K., Koizumi H., Nomura T., Yamamoto S. (1998). Pathological features of spontaneou s induced tumors in transgenic mice carrying a human prototype c-Ha-ras gene used for six-month carcinogenicity studies. Toxicol Pathol 26: 520—531.[Abstract/Free Full Text]
• Miyagawa M., Katsuta O., Chida T., Toyota N., Tsuchitani M., Yoshikawa K., Fujii O. (1998). Occurrence of toxicity and cell proliferation after a single gavage administration of chloroform to male F344 rats. J Toxicol Sci 23: 205—211.[Medline] [Order article via Infotrieve]
• Morris RD, Audet AM, Angelillo IF, Chalmers TC, Mosteller F. (1992). Chlorination, chlorination by-products, and cancer: A meta-analysis. Am J Public Health 82: 955—963.[Abstract/Free Full Text]
• National Cancer Institute ( 1976). Report on carcinogenesi s bioassay of chloroform. NIH 76-1279.
• Ogasawara H., Tsutsumi M., Takeda K., Usui K., Kobayashi H., Murakami H., Takagi H., Kumagai T., Konishi Y. (2000). Utility of transgenic mice carrying human prototype c-Ha-ras gene for alternative carcinogenicity testing of chemicals—negative results with methapyrilene hydrochloride. J Toxicol Pathol 13: 179—188.[CrossRef]
• Robinson D. (1998). The International Life Science Institute's role in the evaluation of alternative methodologies for the assessment of carcinogenic risk. Toxicol Pathol 26: 474—475.[Free Full Text]
• Sagartz JE, Curtiss SW, Bunch RT, Davila JC, Morris DL, Alden CL (1998). Phenobarbital does not promote hepatic tumorigenesi s in a twenty-six-week bioassay in p53 heterozygous mice. Toxiocol Pathol 26: 492—500.
• Saitoh A., Kimura M., Takahashi R., Yokoyama M., Nomura T., Izawa M., Sekiya T., Nishimura S., Katsuki M. (1990). Most tumors in transgenic mice with human c-Ha-ras gene contained somatically activated transgenes. Oncogene 5: 1195—1200.[Web of Science][Medline] [Order article via Infotrieve]
• Shirai K., Uemura Y., Fukumoto M., Tsukamoto T., Pascual R., Nandi S., Tsubura A. (1997). Synergistic effect of MNU and DMBA in mammary carcinogenesis and H-ras activation in female Sprague-Dawley rats. Cancer Lett 120: 87—93.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Tennant RW, French JE, Spalding JW (1995). Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models. Environ Health Perspect 103: 942—950.[Web of Science][Medline] [Order article via Infotrieve]
• Yamamoto S., Hayashi Y., Mitsumori K., Nomura T. (1997). Rapid carcinogenicity testing system with transgenic mice harboring human prototype c-H RAS gene. Lab Anim Sci 47: 121—126.[Web of Science][Medline] [Order article via Infotrieve]
• Yamamoto S., Mitsumori K., Kodama Y., Matsunuma N., Manabe S., Okamiya H., Suzuki H., Fukuda T., Sakamaki Y., Sunaga M., Nomura G., Hioki K., Wakana S., Nomura T., Hayashi Y. (1996). Rapid induction of more malignant tumors by various genotoxic carcinogens in transgenic mice harboring a human prototype c-Ha-ras gene than in control non-transgeni c mice. Carcinogenesis 17: 2455—2461.[Abstract/Free Full Text]

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


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