Skip to main content
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1988 Jan;79(1):49–58. doi: 10.1111/j.1349-7006.1988.tb00010.x

Hepatocellular Tumorigenicity of Butylated Hydroxytoluene Administered Orally to B6C3F1 Mice

Kouki Inai 1, Toshihiro Kobuke 1, Shigeru Nambu 1, Tsuyoshi Takemoto 1, Eihaku Kou 1, Hajime Nishina 1, Megumu Fujihara 1, Shoji Yonehara 1, Shin‐ichi Suehiro 1, Takafumi Tsuya 1, Kenji Horiuchi 1, Shoji Tokuoka 1
PMCID: PMC5907751  PMID: 3128505

Abstract

Butylated hydroxytoluene (BHT), a preservative widely found in food as a food additive, was orally administered at concentrations of 1% and 2% of the diet to B6C3F1 mice for 104 consecutive weeks. Treated animals underwent a 16‐week recovery period prior to pathological examination. In male mice administered BHT, the incidence of mice with either a hepatocellular adenoma or a focus of cellular alteration in the liver was increased in a clear dose‐response relationship. The incidences of male mice with other tumors and the incidences of female mice with any tumor were not significantly increased as a consequence of BHT administration. The results of this study indicate BHT to be tumorigenic to the liver of the B6C3F1 male mouse.

Keywords: BHT, Hepatocellular tumor, B6C3F1 mouse

Full Text

The Full Text of this article is available as a PDF (646.7 KB).

REFERENCES

  • 1).Joint FAO/WHO Expert Committee on Food Additives . Toxicological evaluation of certain food additives . In “ WHO Food Additive Series No. 15 ,” pp . 1 – 151 ( 1980. ). World Health Organization; , Geneva . [Google Scholar]
  • 2).Gilbert , D. and Golberg , L.Liver response tests. III. Liver enlargement and stimulation of microsomal processing enzyme activity . Food Cosmet. Toxicol. , 3 , 417 – 432 ( 1965. ). [DOI] [PubMed] [Google Scholar]
  • 3).National Institutes of Health . Bioassay of butylated hydroxytoluene (BHT) for possible carcinogenicity . In “ NIH 79‐1706 ” ( 1979. ). USDHEW; , Washington , D.C. [Google Scholar]
  • 4).Clapp , N. K. , Tyndall , R. L. and Cumming , R. B.Hyperplasia of hepatic bile ducts in mice following long‐term administration of butylated hydroxytoluene . Food Cosmet. Toxicol. , 11 , 847 – 849 ( 1973. ). [DOI] [PubMed] [Google Scholar]
  • 5).Deichman , W. B. , Clemmer , J. J. , Rakoczy , R. and Bianchine , J.Toxicity of ditertiary‐butylmethylphenol . Arch. Indust. Health , 11 , 93 – 101 ( 1955. ). [PubMed] [Google Scholar]
  • 6).Hirose , M. , Shibata , M. , Hagiwara , A. , Imaida , K. and Ito , N.Chronic toxicity of butylated hydroxytoluene in Wistar rats . Food Cosmet. Toxicol. , 19 , 147 – 151 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 7).Shirai , T. , Hagiwara , A. , Kurata , Y. , Shibata , S. , Fukushima , S. and Ito , N.Lack of carcinogenicity of butylated hydroxytoluene on long‐term administration to B6C3F1 mice . Food Cosmet. Toxicol. , 20 , 861 – 865 ( 1982. ). [DOI] [PubMed] [Google Scholar]
  • 8).Olsen , P. , Meyer , O. , Bille , N. and Würtzen , G.Carcinogenicity study on butylated hydroxytoluene (BHT) in Wistar rats exposed in utero . Food Chem. Toxicol. , 24 , 1 – 12 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 9).Lindenschmidt , R. C. , Tryka , A. P. , Goad , M. E. and Witschi , M. P.The effects of dietary butylated hydroxytoluene on liver and colon tumor development in mice . Toxicology , 38 , 151 – 60 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 10).Moch , R. W.Pathology of BHA‐ and BHT‐ induced lesions . Food Chem. Toxicol. , 24 , 1167 – 1169 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 11).Joner , P. E.Butylhydroxyanisole (BHA), butylhydroxytoluene (BHT) and ethoxyquin (EMQ) tested for mutagenicity . Acta Vet. Scand. , 18 , 187 – 193 ( 1977. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12).Daugherty , J. P. , Davis , S. and Yielding , K. L.Inhibition by butylated hydroxytoluene of excision repair synthesis and semiconservative DNA synthesis . Biochem. Biophys. Res. Commun. , 80 , 963 – 969 ( 1978. ). [DOI] [PubMed] [Google Scholar]
  • 13).Ministry of Health and Welfare of Japan . “ Annual Report of the Cancer Research ,” pp . 1111 – 1120 ( 1979. ). National Cancer Center; , Tokyo . [Google Scholar]
  • 14).Powell , C. J. , Connelly , J. C , Jones , S. M. , Grasso , P. and Bridges , J. W.Hepatic responses to the administration of high doses of BHT to the rat: their relevance to hepatocarcinogenicity . Food Chem. Toxicol. , 24 , 1131 – 1143 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 15).Frith , C. H. and Ward , J. M.A morphologic classification of proliferative and neoplastic hepatic lesions in mice . J. Environ. Pathol. Toxicol. , 3 , 329 – 351 ( 1980. ). [PubMed] [Google Scholar]
  • 16).Ward , J. M. , Goodman , D. G. , Squire , R. A. , Chu , K. C. and Linhart , M. S.Neoplastic and nonneoplastic lesions in aging (C57BL/6N×C3H/HeN)F1 (B6C3F1) mice . J. Natl. Cancer Inst. , 63 , 849 – 854 ( 1979. ). [DOI] [PubMed] [Google Scholar]
  • 17).Haseman , J. K. , Huff , J. and Boorman , G. A.Use of historical control data in carcinogenicity studies in rodents . Toxicol. Pathol. , 12 , 126 – 135 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 18).Kobuke , T. , Inai , K. , Nambu , S. , Ohe , K. , Takemoto , T. , Matsuki , K. , Nishina , H. , Huang , I. B. and Tokuoka , S.Tumorigenicity study of disodium glycyrrhizinate administered orally to mice . Food Chem. Toxicol. , 23 , 979 – 983 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 19).Kumagai , H. , Kawaura , A. , Shibata , M. and Otsuka , H.Carcinogenicity of dipyrone in (C57BL/6×C3H)F1 mice . J. Natl. Cancer Inst. , 71 , 1295 – 1297 ( 1983. ). [PubMed] [Google Scholar]
  • 20).Naito , M. , Ito , A. , Watanabe , H. , Kawashima , K. and Aoyama , H.Carcinogenicity of o‐ethoxybenzamide in (C57BL/6N×C3H/HeN)F1, mice . J. Natl. Cancer Inst. , 76 , 115 – 118 ( 1986. ). [PubMed] [Google Scholar]
  • 21).Peraino , C. , Fry , R. J. M. , Staffeldt , E. and Christopher , J. P.Enhancing effects of phenobarbitone and butylated hydroxytoluene on 2‐acetylaminofluorene‐induced hepatic tumorigenesis in the rat . Food Cosmet. Toxicol. , 15 , 93 – 96 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 22).Maeura , Y. and Williams , G. M.Enhancing effect of butylated hydroxytoluene on the development of liver altered foci and neoplasms induced by N‐2‐fluorenylacetamide in rats . Food Chem. Toxicol. , 22 , 191 – 198 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 23).Clapp , N. K. , Tyndall , R. L. , Cumming , R. B. and Otten , J. A.Effects of butylated hydroxytoluene alone or with diethylnitrosamine in mice . Food Cosmet. Toxicol. , 12 , 367 – 371 ( 1974. ). [DOI] [PubMed] [Google Scholar]
  • 24).Witschi , I. , Williamson , D. and Lack , S.Enhancement of urethan tumorigenesis in mouse lung by butylated hydroxytoluene . J. Natl. Cancer Inst. , 58 , 301 – 305 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 25).Witschi , H. and Morse , C. C.Enhancement of lung tumor formation in mice by dietary butylated hydroxytoluene: dose‐time relationship and cell kinetics . J. Natl. Cancer Inst. , 71 , 859 – 866 ( 1983. ). [PubMed] [Google Scholar]
  • 26).Imaida , K. , Fukushima , S. , Shirai , T. , Masui , T. , Ogiso , T. and Ito , N.Promoting activities of butylated hydroxyanisole, butylated hydroxytoluene and sodium L‐ascorbate on forestomach and urinary bladder carcinogenesis initiated with methylnitrosourea in F344 rats . Gann , 75 , 769 – 775 ( 1984. ). [PubMed] [Google Scholar]
  • 27).Harman , D.Free radical theory of aging: effect of free radical reaction inhibitors on the mortality rate of male LAF1 mice . J. Gerontol. , 23 , 476 – 482 ( 1968. ). [DOI] [PubMed] [Google Scholar]
  • 28).Clapp , N. K. , Satterfield , L. C. and Bowles , N. D.Effects of the antioxidant butylated hydroxytoluene (BHT) on mortality in BALB/C mice . J. Gerontol. , 34 , 497 – 501 ( 1979. ). [DOI] [PubMed] [Google Scholar]
  • 29).Yu , B. P. , Masoro , E. J. , Murata , I. , Bertrand , H. A. and Lynd , F. T.Life span study of SPF Fischer 344 male rats fed ad libitum or restricted diets: longevity, growth, lean body mass and disease . J. Gerontol. , 37 , 130 – 141 ( 1982. ). [DOI] [PubMed] [Google Scholar]
  • 30).Wattenberg , L. W.Inhibition of carcinogenic and toxic effects of polycyclic hydrocarbons by phenolic antioxidants and ethoxyquin . J. Natl. Cancer Inst. , 48 , 1425 – 1430 ( 1972. ). [PubMed] [Google Scholar]
  • 31).Cohen , L. A. , Polansky , M. , Furuya , K. , Reddy , M. , Berke , B. and Weisburger , J. H.Inhibition of chemically induced mammary carcinogenesis in rats by short‐term exposure to butylated hydroxytoluene (BHT): interrelationships among BHT concentration, carcinogen dose and diet . J. Natl. Cancer Inst. , 72 , 165 – 174 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 32).Ulland , B. M. , Weisburger , J. H. , Yamamoto , R. S. and Weisburger , E. K.Antioxidants and carcinogenesis: butylated hydroxytoluene, but not diphenyl‐p‐phenyI‐endiamine inhibits cancer induction by N‐2‐fluorenylacetamide and by N‐hydoxy‐N‐2‐fluorenylacetamide in rats . Food Cosmet. Toxicol. , 11 , 199 – 207 ( 1973. ). [DOI] [PubMed] [Google Scholar]
  • 33).Weisburger , E. K. , Evarts , R. P. and Wenk , M. L.Inhibitory effect of butylated hydroxytoluene (BHT) on intestinal carcinogenesis in rats by azoxymethane . Food Cosmet. Toxicol. , 15 , 139 – 141 ( 1977. ). [DOI] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES