Evaluation of foci of cellular alteration is utilized in short-term and mid-term rat liver models to assess chemicals for potential carcinogenic effects. Such foci are morphologically defined and readily identified by a variety of histological stains. No single morphological marker appears capable of identifying all foci because of their phenotypic heterogeneity. Since most rodent hepatocarcinogens induce an increase in the size and/or the number of foci prior to tumor appearance, foci are believed to be precursors to hepatic tumors. The size, number, phenotype and conversion rate of foci to tumors is chemical dependent. Despite certain limitations, the quantitation of rat liver foci provides a useful means to study the mechanism of action of selected chemicals and assess their carcinogenic potential.
BeerDGPitotHC (1987). Biological markers characterizing the development of preneoplastic and neoplastic lesions in rodent liver. Arch. Toxicol. Suppl.10: 68–80.
2.
CampbellHAPitotHCPotterVRLaishesBA (1982). Application of quantitative stereology to the evaluation of enzyme-altered foci in rat liver. Cancer Res.42: 465–472.
3.
CampbellHAXuY-DHaniganMHPitotHC (1986). Application of quantitative stereology to the evaluation of phenotypically heterogeneous enzyme-altered foci in the rat liver. J. Natl. Cancer Inst.76: 751–767.
4.
CattleyRCPoppJA (1989). Differences between the promoting activities of the peroxisome proliferator WY-14,643 and phenobarbital in rat liver. Cancer Res.49: 3246–3251.
5.
DealPHRichardsonPCSwenbergJA (1987). Dose-response studies on hepatocyte replication following continuous exposure to diethylnitrosamine (DEN). Proc. Am. Assoc. for Cancer Res.28: 85.
6.
DyroffMCRichardsonFCPoppJABedellMASwenbergJA (1986). Correlation of C4-ethyldeoxythymidine accumulation, hepatic initiation and hepatocellular carcinoma induction in rats continuously administered diethylnitrosamine. Carcinogenesis (Lond.)7: 241–246.
7.
EkemJKArmstrongDCameronRC (1989). Identification of the putative first cellular step of chemical hepatocarcinogenesis. Proc. Am. Assoc. for Cancer Res.30: 193.
8.
EmmelotPSchererE (1980). The first relevant cell stage in rat liver carcinogenesis. A quantitative approach. Biochim. et Biophys. Acta605: 247–304.
9.
GarveyLKLyghtOPoppJA (1988). Evaluation of deoxycholic acid (DCA) promotion in rat liver. The Toxicologist8: 195.
10.
GlauertHPSchwarzMPitotHC (1986). The phenotypic stability of altered hepatic foci: Effect of the short-term withdrawal of phenobarbital and of the long-term feeding of purified diets after the withdrawal of phenobarbital. Carcinogenesis7: 117–121.
11.
GlauertHPBeerDRaoMSSchwarzMXuY-DGoldsworthyTLColomaJPitotHC (1986). Induction of altered hepatic foci in rats by the administration of hypolipidemic peroxisome proliferators alone or following a single dose of diethylnitrosamine. Cancer Res.46: 4601–4606.
12.
GoldsworthyTLCampbellHAPitotHC (1984). The natural history and dose-response characteristics of enxyme-altered foci in rat liver following phenobarbital and diethylnitrosamine administration. Carcinogenesis5: 67–71.
13.
GoldsworthyTLPitotHC (1985a). An approach to the development of a short-term whole animal bioassay to distinguish initiating agents (incomplete carcinogens), promoting agents, complete carcinogens, and noncarcinogens in rat liver. J. Toxicol. Environ. Health16: 389–402.
14.
GoldsworthyTLPitotHC (1985b). The quantitative analysis and stability of histochemical markers of altered hepatic foci in rat liver following initiation by diethylnitrosamine administration and promotion with phenobarbital. Carcinogenesis6: 1261–1269.
15.
GoldsworthyTLHammTEJr.RickertDEPoppJA (1986). The effect of diet on 2,6-dinitrotoluene hepatocarcinogenesis. Carcinogenesis7: 1909–1915.
16.
GoldsworthyTLHaniganMHPitotHC (1986). Models of hepatocarcinogenesis in the rat—Contrasts and comparisons. CRC Crit. Rev.17: 61–89.
17.
HendrichSCampbellHAPitotHC (1987). Quantitative stereological evaluation of four histochemical markers of altered foci in multistage hepatocarcinogenesis in the rat. Carcinogenesis8: 1245–1250.
18.
ImaidaKTatematsuMKatoTTsudaHItoN (1989). Advantages and limitations of stereological estimation of placental glutathione S-transferase-positive rat liver cell foci by computerized three-dimensional reconstruction. Jpn. J. Cancer Res.80: 326–330.
19.
ItoNTsudaHTatematsuMInoueTTagawaYAokiTUwagawaSKagawaMOgisoTMasuiTImaidaKFukushimaSAsamatoM (1988). Enhancing effect 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.
20.
KaufmannWKMackenzieSAKaufmanDG (1985). Quantitative relationship between hepatocytic neoplasms and islands of cellular alteration during hepatocarcinogenesis in the male F344 rat. Am. J. Pathol.119: 171–174.
21.
KaufmannWKRahikjaRJMackenzieSAKaufmanDG (1987). Cell cycle-dependent initiation of hepatocarcinogenesis in rats by (±) 7r, 8t-dihydroxy-9t, 10t-epoxy-7,8,9,10-tetrahydrobenzo-(a)pyrene. Cancer Res.47: 3771–3775.
22.
KitagawaTSuganoH (1977). Enhancement of azo-dye hepatocarcinogenesis with dietary phenobarbital in rats. Gann68: 255–256.
23.
LeonardTBDentJGGraichenMELyghtOPoppJA (1982). Comparison of hepatic carcinogen initiation-promotion systems. Carcinogenesis3: 851–856.
24.
LeonardTBAdamsTPoppJA (1986). Dinitrotoluene isomer-specific enhancement of the expression of diethylnitrosamine-initiated hepatocyte foci. Carcinogenesis7: 1797–1803.
25.
LeonardTBGraichenMEPoppJA (1987). Dinitrotoluene isomer-specific hepatocarcinogenesis in F344 rats. J. Natl. Cancer Inst.79: 1313–1319.
26.
MaronpotRRMontgomeryCAJr.BoormanGAMcConnellEE (1986). National Toxicology Program Nomenclature for hepatoproliferative lesions of rats. Toxicol. Pathol.14: 263–273.
27.
MarsmanDSPoppJA (1989). Importance of basophilic hepatocellular foci in the development of hepatic tumors induced by the peroxisome proliferator, Wy-14,643. Proc. Am. Assoc. for Cancer Res.30: 193.
28.
MooreMAKitagawaT (1986). Hepatocarcinogenesis in the rat. The effect of promoters and carcinogens in vivo and in vitro. Int. Rev. Cytol.101: 125–174.
OgawaLSoltDBFarberE (1980). Phenotypic diversity as an early property of putative preneoplastic hepatocyte populations in liver carcinogenesis. Cancer Res.40: 725–733.
31.
PerainoCFryRJMStaffeldtE (1971). Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene. Cancer Res.31: 1506–1512.
32.
PerainoCFryRJMStaffeldtEKisieleskiWE (1973). Effects of varying the exposure to phenobarbital on its enhancement of 2-acetylaminofluorene-induced hepatic tumorigenesis in the rat. Cancer Res.33: 2701–2705.
33.
PerainoCRichardsWLStevensFJ (1983). Multistage Hepatocarcinogenesis. In: Mechanisms of Tumor Promoters, Vol. I. Tumor Promotion in Internal Organs. SlagaTJ (ed). CRC Press Inc., pp. 1–53.
34.
PerainoCStaffeldtEFCarnesBALudemanVABlomquistJAVesselinovitchSD (1984). Characterization of histochemically detectable altered hepatocyte foci and their relationship to hepatic tumorigenesis in rats treated once with diethylnitrosamine or benzo(a)pyrene within one day after birth. Cancer Res.44: 3340–3347.
35.
PerainoCCarnesBAStevensFJ (1986). Evidence for growth heterogeneity among foci with different phenotypes in the population of altered hepatocyte foci induced by a single neonatal treatment with carcinogen. Carcinogenesis7: 191–192.
36.
PitotHCBarsnessLGoldsworthyTKitagawaT (1978). Biochemical characterisation of stages of hepatocarcinogenesis after a single dose of diethylnitrosamine. Nature271: 456–458.
37.
PitotHCSiricaAE (1980). The stages of initiation and promotion in hepatocarcinogenesis. Biochim. Biophys. Acta605: 192–215.
38.
PitotHCGoldsworthyTCampbellHAPolandA (1980). Quantitative evaluation of the promotion by 2,3,7,8-tetrachlorodibenzo-p-dioxin of hepatocarcinogenesis from diethylnitrosamine. Cancer Res.40: 3616–3620.
39.
PitotHCGoldsworthyTMoranSSiricaAEWeeksJ (1982). Properties of incomplete carcinogens and promoters in hepatocarcinogenesis. In: Carcinogenesis, Vol. 7, HeckerE. et al (eds). Raven Press, New York, pp. 85–98.
40.
PitotHCGlauertHPHaniganM (1985). The significance of selected biochemical markers in the characterization of putative initiated cell populations in rodent liver. Cancer Lett.29: 1–14.
41.
PitotHCCampbellHA (1987). An approach to the determination of the relative potencies of chemical agents during the stages of initiation and promotion in multistage hepatocarcinogenesis in the rat. Environ. Health Perspect.76: 49–50.
42.
PitotHCGoldsworthyTLMoranSKennaWGlauertHPMaronpotRRCampbellHA (1987). A method to quantitate the relative initiating and promoting potencies of hepatocarcinogenic agents in their dose-response relationships to altered hepatic foci. Carcinogenesis8: 1491–1499.
43.
PoppJAScortichiniBHGarveyLK (1985). Quantitative evaluation of hepatic foci of cellular alteration occurring spontaneously in Fischer 344 rats. Fund. Appl. Toxicol.5: 314–319.
44.
PughTDGoldfarbS (1978). Quantitative histochemical and autoradiographic studies of hepatocarcinogenesis in rats fed 2-acetylaminofluorene followed by phenobarbital. Cancer Res.38:4450–4457.
45.
PughTDKingJHKoenHNychkaDChoverJWahbaGHeY-HGoldfarbS (1983). Reliable stereological method for estimating the number of microscopic hepatocellular foci from their transections. Cancer Res.43: 1261–1268.
46.
RaoMSLalwaniNDScarpelliDGReddyJK (1982). The absence of γ-glutamyl transpeptidase activity in putative preneoplastic lesions and in hepatocellular carcinomas induced in rats by the hypolipidemic peroxisome proliferator WY-14,643. Carcinogenesis3: 1231–1233.
47.
RaoMSTatematsuMSubbaraoVItoNReddyJK (1986). Analysis of peroxisome proliferator-induced preneoplastic and neoplastic lesions of rat liver for placental form of glutathione S-transferase and γ-glutamyltranspeptidase. Cancer Res.46:5287–5290.
48.
RichardsonFCMorganPHBoucheronJADealFHSwenbergJA (1988). Hepatocyte initiation during continuous administration of diethylnitrosamine and 1,2-sym-dimethylhydrazine. Cancer Res.48: 988–992.
49.
Risk Assessment Forum Document (1986). Proliferative hepatocellular lesions of the rat. RindeEChiuAHillRHabermanB (authors). U.S.E.P.A.Washington, DC.
50.
RussellJJStaffeldtEFWrightBJPrapuolenisACarnesBAPerainoC (1987). Effects of rat strain, diet composition, and phenobarbital on hepatic γ-glutamyl transpeptidase histochemistry and on the induction of altered hepatocyte foci and hepatic tumors by diethylnitrosamine. Cancer Res.47: 1130–1134.
51.
SatoKKitaharaASatohKIshikawaTTatematsuMItoN (1984). The placental form of glutathione S-transferase as a new marker protein for preneoplasia in rat chemical hepatocarcinogenesis. Gann75: 199–202.
SchererEEmmelotP (1975). Foci of altered liver cells induced by a single dose of diethylnitrosamine and partial hepatectomy: Their contribution to hepatocarcinogenesis in the rat. Eur. J. Cancer11:145–154.
54.
SchererEFeringaAWEmmelotP (1984). Initiation-promotion-initiation. Induction of neoplastic foci within islands of precancerous liver cells in the rat. In: Models, Mechanisms and Etiology of Tumor Promotion, BorzsonyiMLapisKDayNEYamasakiH (eds). Lyon, International Agency for Research on Cancer.
55.
SellsMAKatyalSISellSShinozukaHLombardiB (1979). Induction of foci of altered, γ-glutamyl-transpeptidase-positive hepatocytes in carcinogen-treated rats fed a choline-deficient diet. Br. J. Cancer40: 274–283.
56.
SoltDBCayamaESarmaDSRFarberE (1980). Persistence of resistant putative preneoplastic hepatocytes induced by N-nitrosodiethylamine or N-methyl-N-nitrosourea. Cancer Res.40:1112–1118.
57.
SquireRALevittMH (1975). Report of a workshop on classification of specific hepatocellular lesions in rats. Cancer Res.35: 3214–3223.
58.
StewartHLWilliamsGKeysserCHLombardLSMontaliRJ (1980). Histologic typing of liver tumors of the rat. J. Natl. Cancer Inst.64: 179–206.
59.
TatematsuMMeraYItoNSatohKSatoK (1985). Relative merits of immunohistochemical demonstration of placental, A, B and C forms of glutathione S-transferase and histochemical demonstration of gamma glutamyl transpeptidase as markers of altered foci during liver carcinogenesis in rats. Carcinogenesis6: 1621–1626.
60.
TsudaHLeeGFarberE (1980). Induction of resistant hepatocytes as a new principle for a positive short-term in vivo test for carcinogens. Cancer Res.40: 1157–1164.
61.
WatanabeKWilliamsGM (1978). Enhancement of rat hepatocellular-altered foci by the liver tumor promoter phenobarbital: Evidence that foci are precursors of neoplasms and that the promoter acts on carcinogen-induced lesions. J. Natl. Cancer Inst.61: 1311–1314.
62.
WilliamsGMWatanabeK (1978). Quantitative kinetics of development of n-2-fluorenylacetamide-induced, altered (hyperplastic) hepatocellular foci resistant to iron accumulation and of their reversion or persistence following removal of carcinogen. J. Natl. Cancer Inst.61: 113–118.
