Review Article: A Medium-Term Rat Liver Bioassay as a Rapid In Vivo Test for Carcinogenic Potential: A Historical Review of Model Development and Summary of Results from 291 Tests
Free accessReview articleFirst published online September, 1997
Review Article: A Medium-Term Rat Liver Bioassay as a Rapid In Vivo Test for Carcinogenic Potential: A Historical Review of Model Development and Summary of Results from 291 Tests
A bioassay system for rapid detection of carcinogenic agents has been developed using male Fischer 344 rats to bridge the gap between long-term carcinogenicity tests and short-term screening assays. The system, called the medium-term liver bioassay, is fundamentally based on the 2-stage hypothesis of tumor production, employing initiation by diethylnitrosamine (200 mg/kg, ip) in the first stage and test chemical administration during the second, in combination with two-thirds partial hepatectomy. It requires only 8 wk for animal experimentation and a further few weeks for quantitative analysis of immunohistochemically demonstrated glutathione S-transferase placental form positive hepatic foci. A total of 291 chemicals/substances have already been analyzed in our laboratory. Among 63 chemicals that were proved to be carcinogenic in the liver of rat and/or mouse, 57 (90%) gave positive results irrespective of their mutagenicity. Negative compounds include peroxisome proliferators and tamoxifen. Even nonhepatocarcinogens were positive at a rate of 24%. Eighty-six percent (12/14) of mouse liver carcinogens were also positive. On the other hand, only 2 out of 45 noncarcinogens showed very weak positivity. Thus, the efficacy of the system for hepatocarcinogens has been well established. This bioassay is increasingly regarded as an appropriate alternative test for carcinogenicity risk assessment and is practically used for a rapid evaluation of hepatocarcinogenicity of chemicals.
Asamoto M., Tsuda H., Kagawa M., de Camargo JLV, Ito N., and Nagase S. (1989). Strain difference in susceptibility to 2-acetylaminofluorene and phenobarbital promotion of rat hepatocarcinogenesis in a medium-term assay system. Jpn. J. Cancer Res. 80: 939-944.
2.
Ashby J., Brady A., Elcombe CR, Elliott BM, Ishmael J., Odun J., Tugwood JD, Kettle S., and Purchase IFH (1994). Mechanisticallybased human hazard assessment of peroxisome proliferator-induced hepatocarcinogenesis . Hum. Exp. Toxicol. 13(suppl. 2): S1-S117.
3.
Bannasch P. (1986). Preneoplastic lesions as end points in carcinogenicity testing. I. Hepatic neoplasia. Carcinogenesis7: 689-695.
4.
Bentley P., Calder I., Elcombe C., Grasso P., Stringer D., and Wiegand HJ (1993). Hepatic peroxisome proliferation in rodents and its significance for humans. Food Chem. Toxicol. 31: 857-907.
5.
Cabral R., Hoshiya T., Hakoi K., Hasegawa R., and Ito N. (1996) Medium-term bioassay for the hepatocarcinogenicity of hexachlorobenzene. Cancer Lett. 100: 223-226.
6.
de Gerlache J., Lans M., Preat V., Taper H., and Roberfroid M. (1984). Comparison of different models of rat liver carcinogenesis: Conclusions from a systemic analysis. Toxicol. Pathol. 12: 374-382.
7.
Doll R. (1988). Epidemiology and the prevention of cancer: Some recent developments. J. Cancer Res. Clin. Oncol. 114: 447-458.
8.
Dragan YP, Rizvi T., Xu YH, Hully JR, Bawa N., Campbell HA, Maronpot RR, and Pitot H. (1991). An initiation-promotion assay in rat liver as a potential complement to the 2-year carcinogenicity bioassay. Fundam. Appl. Toxicol. 16: 525-547.
9.
Hasegawa R., Cabral R., Hoshiya T., Hakoi K., Ogiso T., Boonyaphiphat P., Shirai T., and Ito N. (1993). Carcinogenic potential of some pesticides in a medium-term multi-organ bioassay in rats. Int. J. Cancer54: 489-493.
10.
Hasegawa R. and Ito N. (1992). Liver medium-term bioassay in rats for screening of carcinogens and modifying factors in hepatocarcinogenesis . Food Chem. Toxicol. 30: 979-992.
11.
Hasegawa R. , Takahashi S., Imaida K., Yamaguchi S., Shirai T., and Ito N. (1991). Age-dependent induction of preneoplastic liver cell foci by 2-acetylaminofluorene, phenobarbital and acetaminophen in F344 rat initially treated with diethylnitrosamine. Jpn. J. Cancer Res. 82: 293-297.
12.
Hasegawa R. , Takahashi S., Shirai T., Iwasaki S., Kim DJ, Ochiai M., Nagao M., Sugimura T., and Ito N. (1992). Dose-dependent formation of preneoplastic foci and DNA adducts in rat liver with 2-amino-3-methyl-9-pyrido[2,3-b]indole (MeAαC) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Carcinogenesis13: 1427-1431.
13.
Hasegawa R. , Tsuda H., Shirai T., Kurata Y., Masuda A., and Ito N. (1986). Effect of timing of partial hepatectomy on the induction of preneoplastic liver foci in rats given hepatocarcinogens . Cancer Lett. 32: 15-23.
14.
Hirose M., Hoshiya T., Akagi K.Takahashi S.Hara Y. and Ito N. (1993). Effects of green tea catechins in a rat multi-organ carcinogenesis model. Carcinogenesis14: 1549-1553.
15.
Hirose M.Shirai T.Tsuda H.Fukushima S.Ogiso T. and Ito N. (1981). Effect of phenobarbital. polychlorinated biphenyl and sodium saccharin on hepatic and renal carcinogenesis in unilaterally nephrectomized rats given N-ethyl-N-hydroxyethylnitrosamine orally. Carcinogenesis2: 1299-1302.
16.
Hirsimaki P.Hirsimaki Y.Nieminen L. and Payne BJ (1993). Tamoxifen induces hepatocellular carcinoma in rat liver: A 1 year study with two antiestrogens. Arch. Toxicol. 67: 49-54.
17.
Horn DMJordan WHHolloway DCSmith WC and Richardson FC (1996). Dose-dependent induction of GST-P+ staining foci by the rat hepatocarcinogen methapyrilene in the medium-term bioassay. Fundam. Appl. Toxicol. 29: 194-197.
18.
Hoshiya T.Hasegawa R.Hakoi K., Cui L., Ogiso T.Cabral R. and Ito N. (1993). Enhancement by non-mutagenic pesticides of GST-P positive hepatic foci development initiated with diethylnitrosamine in the rat. Cancer Lett. 72: 59-64.
19.
Imaida K., Shirai T.Tatematsu M.Takano T., and Ito N. (1981). Dose responses of five hepatocarcinogens for the initiation of rat hepatocarcinogenesis. Cancer Lett. 14: 279-283.
20.
International Conference. Proceedings of the Third International Conference on Harmonisation, 1995. Yokohama, Japan. PF D'Arch and DWG Harron (eds.). Queen's University, Belfast.
21.
Ito N., Hasegawa R.Imaida K., Hirose M.Shirai T., Tamano S. and Hagiwara A. (1997). Medium-term rat liver bioassay for rapid detection of hepatocarcinogenic substances. J. Toxicol. Pathol. 10: 1-11.
22.
Ito N., Hasegawa R., Imaida K., Kurata Y., Hagiwara A., and Shirai T. (1995). Effect of ingestion of 20 pesticides in combination at acceptable daily intake levels on rat liver carcinogenesis. Food Chem. Toxicol. 33: 159-163.
23.
Ito N., Imaida K., Hasegawa R., and Tsuda H. (1989). Rapid bioassay methods for carcinogens and modifiers of hepatocarcinogenesis. CRC Crit. Rev. Toxicol. 19: 385-415.
24.
Ito N., Shirai T., and Hasegawa R. (1992). Medium-term bioassay for carcinogens. In: Mechanisms of Carcinogenesis in Risk Assessment, H Vainio, PN Magee, DB McGregor, and AJ McMichael (eds). IARC Scientific Publications, No.116, IARC, Lyon, pp. 345-380.
25.
Ito N., Tatematsu M., Hasegawa R., and Tsuda H. (1989). Medium-term bioassay system for detection of carcinogens and modifiers of hepatocarcinogenesis utilizing the GST-P positive liver cell focus as an endpoint marker. Toxicol. Pathol. 17: 630-641.
26.
Ito N., Tatematsu M., Imaida K., Hasegawa R., and Murasaki G. (1980). Effects of various promoters on the induction of hyperplastic nodules in rat liver. Gann71: 415-416.
27.
Ito N., Tatematsu M., Nakanishi K., Hasegawa R., Takano T., Imaida K., and Ogiso T. (1980). The effects of various chemicals on the development of hyperplastic liver nodules in hepatectomized rats treated with N-nitrosodiethylamine or N-2-fluorenylacetamide. Gann71: 832-842.
28.
Ito N., Tsuda H., Tatematsu M., Inoue T., Tagawa Y., Aoki T., Uwagawa S., Kagawa M., Ogiso T.Masui T.Imaida K., Fukushima S., and Asamoto M. (1988). Enhancing effects of various hepatocarcinogens on induction of preneoplastic glutathione S-transferase placental form positive foci in rats-An approach for a new medium-term bioassay system. Carcinogenesis9: 387-394.
29.
Jang JJ, Cho KJ, Lee YS and Bae JH (1991). Modifying responses of allyl sulfide, indole-3-carbinol and germanium in a rat multiorgan carcinogenesis model. Carcinogenesis12: 691-695.
30.
Kato T., Hasegawa R., Nakae D.Hirose M., Yaono M., Cui L., Kobayashi Y., Konishi Y.Ito N. and Shirai T. (1996). Dose-dependent induction of 8-hydroxyguanine and preneoplastic foci in rat liver by a food-derived carcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoline. at low dose levels. Jpn. J. Cancer Res.87: 127-133.
31.
Ki DJLee KK, Han BSAhn B.Bae JH and Jang JJ (1994). Biphasic modifying effect of indole-3-carbinol on diethylnitrosamine-induced preneoplastic glutathione S-transferase placental form-positive liver cell foci in Sprague-Dawley rats. Jpn. J. Cancer Res. 85: 578-583.
32.
Miller HI (1994). A need to reinvent biotechnology regulation at the EPA. Science266: 1815-1818.
33.
Oesterle D. and Deml E. (1990). Detection of chemical carcinogens by means of the rat liver bioassay. Exp. Pathol. 39: 197-206.
34.
Ogawa K.Hasegawa R., Wada S., Yamaguchi S., and Ito N. (1992). Dose response study of N-nitrosodiethanolamine for initiation of rat hepatocarcinogenesis. Teratog. Carcinog. Mutagen. 11: 245-250.
35.
Ogiso T.Tatematsu M.Tamano S., Tsuda H., and Ito N. (1985). Comparative effects of carcinogens on the induction of placental glutathione S-transferase-positive liver nodules in a short-term assay and of hepatocellular carcinomas in a long-term assay. Toxicol. Pathol. 13: 257-263.
36.
Peraino C., Fry RJM, and Staffeldt E. (1971). Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene. Cancer Res. 31: 1506-1512.
37.
Sano M., Hagiwara A., Hasegawa R., Tamano S., Ito N., and Shirai T. (1997). Dose response study of di(2-ethylhexyl)phtalate induced rat hepato-carcinogenesis. Proc. Jpn. Cancer Assoc . 55: 263
38.
Sato K., Kitahara A., Satoh K., Ichikawa T., Tatematsu M., and Ito N. (1984). The placental form of glutathione S-transferase as a new marker protein for preneoplasia in rat chemical carcinogenesis. Gann75: 199-202.
39.
Shibata MA, Hasegawa R., Imaida K., Hagiwara A., Ogawa K., Hirose M., Ito N., and Shirai T. (1995). Chemoprevention by dehydroepiandrosterone and indomethacin in a rat multiorgan carcinogenesis model. Cancer Res. 55: 4870-4874.
40.
Shirai T., Imaida K., Ohshima M., Fukushima S., Lee MS, King MC, and Ito N. (1985). Different responses to phenobarbital promotion in the development of γ-glutamyl transpeptidase-positive foci in the liver of rats initiated with diethylnitrosamine, N-hydroxy-2-acetylaminofluorene and aflatoxin B1. Jpn. J. Cancer Res. 76: 16-19.
41.
Shirai T., Masuda A., Imaida K., Ogiso T., and Ito N. (1988). Effects of phenobarbital and carbazole on carcinogenesis of the lung, thyroid, kidney, and bladder of rats pretreated with N-bis(2-hydroxypropyl)nitrosamine. Jpn. J. Cancer Res. 79: 460-465.
42.
Shirose K., Hirose M., and Ito N. (1985). Promotion effects of phenobarbital and 3'-methyl-4-dimethylaminoazobenzene on the appearance of γ-glutamyl transpeptidase positive foci in rat liver pretreated with varying doses of diethylnitrosamine. Cancer Lett. 28: 127-133.
43.
Solt D. and Farber E. (1976). New principle for the analysis of chemical carcinogenesis . Nature263: 701-703.
44.
Staffa JA and Mehlman MA (eds) (1980). Innovation in cancer risk assessment (ED01 study). J. Environ. Pathol. Toxicol . 3: 1-246.
45.
Tamano S., Tsuda H., Fukushima S., Masui T., Hosoda K., and Ito N. (1983). Dose and sex dependent effects of 2-acetylaminofluorene, 3'-methyl-4-dimethylaminoazobenzene and DL-ethionine in induction of γ-glutamyl transpeptidase-positive liver cell foci in rats. Cancer Lett . 20: 313-321.
46.
Tatematsu M. , Hasegawa R., Imaida K., Tsuda H., and Ito N. (1983). Survey of various chemicals for initiating and promoting activities in a short-term in vivo system based on generation of hyperplastic liver nodules in rats. Carcinogenesis4: 381-386.
47.
Tatematsu M. , Mera Y.Inoue T., Satoh K., Sato K., and Ito N. (1988). Stable phenotypic expression of glutathione S-transferase placental type and unstable phenotypic expression of γ-glutamyltransferase in rat liver preneoplastic and neoplastic lesions . Carcinogenesis9: 215-220.
48.
Tatematsu M. , Mera Y., Ito N., Satoh K., and Sato K. (1985). Relative merits of immunohistochemical demonstration of placental A, B and C forms of glutathione S-transferase and histochemical demonstration of γ-glutamyl transferase as markers of altered foci during liver carcinogenesis in rats . Carcinogenesis6: 1621-1626.
49.
Tatematsu M. , Murasaki G., Nakanishi K., Miyata Y., Shinohara Y., and Ito N. (1979). Sequential quantitative studies on hyperplastic nodules in the liver of rats treated with carcinogenic chemicals. Gann70: 125-130.
50.
Tatematsu M. , Shirai T., Tsuda H., Miyata Y., Shinohara Y., and Ito N. (1977). Rapid production of hyperplastic liver nodules in rats treated with carcinogenic chemicals: A new approach for an in vivo short-term screening test for hepatocarcinogens . Gann68: 499-507.
51.
Tiwawech D. , Hasegawa R., Kurata Y., Tatematsu M., Shibata MA, Thamavit W., and Ito N. (1991). Dose-dependent effects of 2-acetylaminofluorene on hepatic foci development and cell proliferation in rats. Carcinogenesis12: 985-990.
52.
Tsuda H., Moore MA, Asamoto M., Inoue T., Ito N., Sato K., Ichihara A., Nakamura T., Amelizad Z., and Oesch F. (1988). Effect of modifying agents on the phenotypic expression of cytochrome P-450, glutathione S-transferase molecular forms, microsomal epoxide hydrolase, glucose-6-phosphate dehydrogenase and γ-glutamyltranspeptidase in rat liver preneoplastic lesions. Carcinogenesis9: 547-554.
53.
Ward JM and Ito N. (1988). Development of new medium-term bioassays for carcinogens . Cancer Res. 48: 5051-5054.
54.
Yaono M., Hasegawa R., Mizoguchi Y., Futakuchi M., Nakamura K., Ito N., and Shirai T. (1995). Hepatocyte growth factor enhancement of preneoplastic hepatic foci development in rats treated with diethylnitrosamine and N-ethyl-N-hydroxyethylnitrosamine. Jpn. J. Cancer Res. 86: 718-723.
