Neonatal mouse assay for tumorigenicity: alternative to the chronic rodent bioassay.

The chronic rodent bioassay for tumors has been utilized systematically for 25 years to identify chemicals with carcinogenic potential in man. In general, those chemicals exhibiting tumorigenicity at multiple sites in both mice and rats have been regarded as possessing strong carcinogenic potential in humans. In comparison, the value of data collected for those test chemicals exhibiting more sporadic tumorigenicity results (e.g., single species/single sex or dose-independent) has been questioned. As knowledge of the carcinogenic process has increased, several alternative test systems, usually faster and less expensive than the 2-year bioassay, have been suggested for identification of the strongly acting, transspecies carcinogens. The International Conference on Harmonization for Technical Requirements for the Registration of Pharmaceuticals for Human Use has proposed an international standard that allows for the use of one long-term rodent carcinogenicity study, plus one supplementary study to identify potential human pharmaceutical carcinogens. The neonatal mouse assay for tumorigenicity has been used since 1959; however, relative to other alternate tests, little has been written about this system. It is clear that this assay system successfully identifies transspecies carcinogens from numerous chemical classes, thus recommending itself as a strong candidate for a supplementary study to identify potential human carcinogens. In contrast, there are decidedly less data available from this assay in response to pharmaceuticals shown to exhibit weak and/or conflicting results in the 2-year bioassay, knowledge invaluable to the regulatory process. This paper reviews the historical development and our experience with the neonatal mouse assay and includes suggestions for a standardized protocol and strategies to document its response to "weak" and/or "nongenotoxic" carcinogens.

[1]  P. Fu,et al.  Comparative carcinogenicity of 4-aminobiphenyl and the food pyrolysates, Glu-P-1, IQ, PhIP, and MeIQx in the neonatal B6C3F1 male mouse. , 1992, Cancer letters.

[2]  J. Mirsalis.  Transgenic models for detection of mutations in tumors and normal tissues of rodents. , 1995, Toxicology letters.

[3]  A. Meister,et al.  Glutathione deficiency decreases tissue ascorbate levels in newborn rats: ascorbate spares glutathione and protects. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[4]  D Y Lai,et al.  Evaluation of reduced protocols for carcinogenicity testing of chemicals: report of a joint EPA/NIEHS workshop. , 1994, Regulatory toxicology and pharmacology : RTP.

[5]  B. Tóth.  A critical review of experiments in chemical carcinogensis using newborn animals. , 1968, Cancer research.

[6]  L. Bernstein,et al.  Interspecies extrapolation in carcinogenesis: prediction between rats and mice. , 1989, Environmental health perspectives.

[7]  Saccharin: past, present, and future. , 1986 .

[8]  S. Hecht,et al.  Metabolism and DNA binding of 1-nitropyrene and 1-nitrosopyrene in newborn mice. , 1988, Chemical research in toxicology.

[9]  S. Vesselinovitch,et al.  Significance of newborn age and dose of urethan in leukemogenesis. , 1966, Cancer research.

[10]  J. Ashby,et al.  Chemicals for evaluating the sensitivity and specificity of reduced/transgenic rodent cancer bioassay protocols. , 1995, Mutation research.

[11]  M. Kelly,et al.  Induction of tumors in newborn mice with dibenz[a, h]anthracene and 3-methylcholanthrene. , 1961, Journal of the National Cancer Institute.

[12]  K. Rao,et al.  Neoplastic response of mouse tissues during perinatal age periods and its significance in chemical carcinogenesis. , 1979, National Cancer Institute monograph.

[13]  B. Butterworth,et al.  Consideration of both genotoxic and nongenotoxic mechanisms in predicting carcinogenic potential. , 1990, Mutation research.

[14]  N. Drinkwater.  Genetic control of hepatocarcinogenesis in C3H mice. , 1994, Drug metabolism reviews.

[15]  J I Goodman,et al.  A rational approach to risk assessment requires the use of biological information: an analysis of the National Toxicology Program (NTP), final report of the advisory review by the NTP Board of Scientific Counselors. , 1994, Regulatory toxicology and pharmacology : RTP.

[16]  S. Cohen.  Cell proliferation in the bladder and implications for cancer risk assessment. , 1995, Toxicology.

[17]  Vesselinovitch Sd.  Perinatal mouse liver carcinogenesis as a sensitive carcinogenesis model and the role of the sex hormonal environment in tumor development. , 1990 .

[18]  J. Westra,et al.  Comparative carcinogenicity of the food pyrolysis product, 2-amino-5-phenylpyridine, and the known human carcinogen, 4-aminobiphenyl, in the neonatal B6C3F1 mouse. , 1988, Cancer letters.

[19]  U. Thorgeirsson,et al.  Tumor incidence in a chemical carcinogenesis study of nonhuman primates. , 1994, Regulatory toxicology and pharmacology : RTP.

[20]  L. Gold,et al.  Ranking possible carcinogenic hazards. , 1987, Science.

[21]  A. Meister,et al.  Glutathione deficiency increases hepatic ascorbic acid synthesis in adult mice. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[22]  E. LaVoie,et al.  Tumorigenic activity of the 4,5- and 9,10-dihydrodiols of benzo[j]fluoranthene and their syn- and anti-diol epoxides in newborn mice. , 1994, Cancer research.

[23]  S. Hecht,et al.  Metabolism of the carcinogen [3H]6-nitrochrysene in the preweanling mouse: identification of 6-aminochrysene-1,2-dihydrodiol as the probable proximate carcinogenic metabolite. , 1988, Carcinogenesis.

[24]  GIUSEPPE PIETRA,et al.  Response of Newly Born Mice to a Chemical Carcinogen , 1959, Nature.

[25]  B. Ames,et al.  Too many rodent carcinogens: mitogenesis increases mutagenesis. , 1990, Science.

[26]  S. Hecht,et al.  Metabolism of benzo[a]pyrene and 7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene in lung and liver of newborn mice , 1989 .

[27]  M. Walters.  The induction of lung tumours by the injection of 9,10-dimethyl-1,2-benzanthracene (DMBA) into newborn suckling and young adult mice. A dose response study. , 1966, British Journal of Cancer.

[28]  B. Terracini,et al.  Chemical carcinogenesis in infant animals. , 1969, Progress in experimental tumor research.

[29]  P. Fu,et al.  Inhibitory effect of caloric restriction on tumorigenicity induced by 4-aminobiphenyl and 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) in the CD1 newborn mouse bioassay. , 1996, Cancer letters.

[30]  N. Drinkwater,et al.  Rapid growth of preneoplastic lesions in hepatocarcinogen-sensitive C3H/HeJ male mice relative to C57BL/6J male mice. , 1988, Carcinogenesis.

[31]  Michael F. W. Festing,et al.  Use of a Multistrain Assay Could Improve the NTP Carcinogenesis Bioassay , 1995 .

[32]  B. Tóth,et al.  Influence of Dose and Age on the Induction of Malignant Lymphomas and Other Tumors by 7,12-Dimethylbenz[α]anthracene in Swiss Mice , 1963 .

[33]  K. Kolaja,et al.  Oxidative stress in nongenotoxic carcinogenesis. , 1995, Toxicology letters.

[34]  W. Welshons,et al.  Estrogenic pesticides: binding relative to estradiol in MCF-7 cells and effects of exposure during fetal life on subsequent territorial behaviour in male mice. , 1995, Toxicology letters.

[35]  A. Y. Lu,et al.  Tumorigenicity of nitrated derivatives of pyrene, benz[a]anthracene, chrysene and benzo[a]pyrene in the newborn mouse assay. , 1986, Carcinogenesis.

[36]  B. Lake.  Peroxisome proliferation: current mechanisms relating to nongenotoxic carcinogenesis. , 1995, Toxicology letters.

[37]  H. Rappaport,et al.  The effects of carcinogenic chemicals in newborn mice , 1961, Cancer.

[38]  E C Miller,et al.  Structure-activity studies of the hepatocarcinogenicities of alkenylbenzene derivatives related to estragole and safrole on administration to preweanling male C57BL/6J x C3H/HeJ F1 mice. , 1987, Cancer research.

[39]  L. Chieco‐Bianchi,et al.  Influence of Age on Susceptibility to Liver Carcinogenesis and Skin Initiating Action by Urethane in Swiss Mice , 1963, British Journal of Cancer.

[40]  J. Weisburger.  Does the Delaney Clause of the U.S. Food and Drug Laws Prevent Human Cancers , 1994 .

[41]  J. Goodman,et al.  Hypomethylation of DNA: a possible epigenetic mechanism involved in tumor promotion. , 1995, Progress in clinical and biological research.

[42]  J. Huff,et al.  The carcinogenesis bioassay in perspective: application in identifying human cancer hazards. , 1995, Environmental health perspectives.

[43]  D. Gaylor.  Comparison of teratogenic and carcinogenic risks. , 1989, Regulatory toxicology and pharmacology : RTP.

[44]  A. Balmain,et al.  Transgenic approaches to understanding the mechanisms of chemical carcinogenesis in mouse skin. , 1995, Toxicology letters.

[45]  J. Liehr,et al.  Free radical generation by redox cycling of estrogens. , 1990, Free radical biology & medicine.

[46]  V. Krutovskikh,et al.  Role of blocked gap junctional intercellular communication in non-genotoxic carcinogenesis. , 1995, Toxicology letters.

[47]  E. V. Cowdry,et al.  The Role of Sebaceous Glands and Hair Follicles in Epidermal Carcinogenesis , 1947 .

[48]  D. Clive,et al.  The potent hepatocarcinogen methapyrilene induces mutations in L5178Y mouse lymphoma cells in the apparent absence of DNA adduct formation. , 1991, Mutation research.

[49]  F. W. Carlborg,et al.  Evaluation of the dose response and in utero exposure to saccharin in the rat. , 1985, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[50]  A. Conney,et al.  Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: G. H. A. Clowes Memorial Lecture. , 1982, Cancer research.

[51]  M. Gross,et al.  Molecular characteristics of catechol estrogen quinones in reactions with deoxyribonucleosides. , 1996, Chemical research in toxicology.

[52]  S. J. James,et al.  Rates of apoptosis and proliferation vary with caloric intake and may influence incidence of spontaneous hepatoma in C57BL/6 x C3H F1 mice. , 1994, Cancer research.

[53]  J. Contrera,et al.  Carcinogenicity testing and the evaluation of regulatory requirements for pharmaceuticals. , 1997, Regulatory toxicology and pharmacology : RTP.

[54]  H. Issaq,et al.  Promotion by polychlorinated biphenyls of lung and liver tumors in mice. , 1994, Carcinogenesis.

[55]  P. Fu,et al.  Caloric restriction profoundly inhibits liver tumor formation after initiation by 6-nitrochrysene in male mice. , 1994, Carcinogenesis.

[56]  R. Tennant,et al.  Stratification of rodent carcinogenicity bioassay results to reflect relative human hazard. , 1993, Mutation research.

[57]  P. Fu,et al.  Potent tumorigenicity of 7-chlorobenz[a]anthracene and 7-bromobenz[a]anthracene in the neonatal B6C3F (1) male mouse. , 1996, Cancer letters.

[58]  S. Vesselinovitch,et al.  Histochemical characterization of focal hepatic lesions induced by single diethylnitrosamine treatment in infant mice. , 1985, Cancer research.

[59]  N. Drinkwater,et al.  Genetic determinants of hepatocarcinogenesis in the B6C3F1 mouse. , 1989, Toxicology letters.

[60]  A. Meister,et al.  Mitochondrial changes associated with glutathione deficiency. , 1995, Biochimica et biophysica acta.

[61]  J. Miller,et al.  4-aminoazobenzene and N,N-dimethyl-4-aminoazobenzene as equipotent hepatic carcinogens in male C57BL/6 X C3H/He F1 mice and characterization of N-(Deoxyguanosin-8-yl)-4-aminoazobenzene as the major persistent hepatic DNA-bound dye in these mice. , 1984, Cancer research.

[62]  J. Haseman,et al.  Growth, Body Weight, Survival, and Tumor Trends in (C57BL/6 X C3H/HeN) F1 (B6C3F1) Mice during a Nine-Year Period , 1990, Toxicologic pathology.

[63]  J. Leakey,et al.  FDA Points-to-Consider Documents: The Need for Dietary Control for the Reduction of Experimental Variability within Animal Assays and the Use of Dietary Restriction to Achieve Dietary Control , 1996, Toxicologic pathology.

[64]  J. Miller,et al.  Sulfuric acid esters as major ultimate electrophilic and hepatocarcinogenic metabolites of 4-aminoazobenzene and its N-methyl derivatives in infant male C57BL/6J x C3H/HeJ F1 (B6C3F1) mice. , 1986, Carcinogenesis.

[65]  Vesselinovitch Sd.  Infant mouse as a sensitive bioassay system for carcinogenicity of N-nitroso compounds. , 1980 .

[66]  M. Hollinger,et al.  CRC handbook of toxicology , 1995 .

[67]  K Fujii.  Evaluation of the newborn mouse model for chemical tumorigenesis. , 1991, Carcinogenesis.

[68]  R. Robertson,et al.  Dietary restriction : implications for the design and interpretation of toxicity and carcinogenicity studies , 1995 .