The use of genetically modified mice in cancer risk assessment: Challenges and limitations

Critical Reviews in Toxicology

Volumn 43, Issue 8, 2013, Pages 611-631

  Eastmond, David A ^a   Vulimiri, Suryanarayana V ^b   French, John E ^c   Sonawane, Babasaheb ^b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b U S ENVIRONMENTAL PROTECTION AGENCY   (United States)

^c NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES   (United States)

Author keywords

Carcinogen; Concordance; Dose response; Hazard identification; Mechanism; Pathway specificity; Study duration; Transgenic

Indexed keywords

1,1,2 TRICHLOROETHANE; 2 IMIDAZOLIDINETHIONE; 2,3,7,8 TETRACHLORODIBENZO PARA DIOXIN; 2,4 DIAMINOTOLUENE; 4,4' THIODIANILINE; 6 NITROBENZIMIDAZOLE; 7,12 DIMETHYLBENZ[A]ANTHRACENE; ACRYLIC ACID ETHYL ESTER; BENZENE; BENZOYL PEROXIDE; BROMODICHLOROMETHANE; CARCINOGEN; CHLOROFORM; CHLOROPRENE; DIETHANOLAMINE; DIMETHYLVINYL CHLORIDE; DIOXANE; FURFURAL; FURFURYL ALCOHOL; GLYCIDOL; LAURIC ACID DIETHANOLAMINE; METHYLOLACRYLAMIDE; METHYLPHENIDATE; PENTACHLOROPHENOL; PHENOLPHTHALEIN; PROCARBAZINE; PYRIDINE; RESERPINE; THIOTEPA; UNCLASSIFIED DRUG; URETHAN;

ANGIOSARCOMA; B CELL LYMPHOMA; BIOASSAY; BLADDER CANCER; BREAST CARCINOMA; CANCER INCIDENCE; CANCER MODEL; CANCER RISK; CARCINOGENIC ACTIVITY; CARCINOGENICITY; CARCINOMA; CARCINOSARCOMA; CHEMICAL CARCINOGENESIS; DOSE RESPONSE; EXPERIMENTAL MODEL; EXPERIMENTAL RAT; EXPOSURE; GENOMIC INSTABILITY; HAPLOINSUFFICIENCY; HEMATOLOGIC MALIGNANCY; HUMAN; LEUKEMIA; LIVER CANCER; LUNG ADENOCARCINOMA; LUNG ADENOMA; LYMPHOMA; MOUSE; MOUSE STRAIN; NONHUMAN; ONCOGENE; OSTEOSARCOMA; OVARY CANCER; REPRODUCIBILITY; REVIEW; RISK ASSESSMENT; SAFETY; SAMPLE SIZE; SARCOMA; SKIN CANCER; SOFT TISSUE SARCOMA; T CELL LYMPHOMA; TRANSGENIC MOUSE; VALIDATION PROCESS;

ANIMALS; CARCINOGENICITY TESTS; CARCINOGENS; DISEASE MODELS, ANIMAL; DOSE-RESPONSE RELATIONSHIP, DRUG; MICE; MICE, TRANSGENIC; NEOPLASMS; REPRODUCIBILITY OF RESULTS; RISK ASSESSMENT;

EID: 84883363371     PISSN: 10408444     EISSN: 15476898     Source Type: Journal    
DOI: 10.3109/10408444.2013.822844     Document Type: Review

References (140)

1. Anderson EL. (1983). Quantitative approaches in use to assess cancer risk. Risk Anal, 3, 277-95.
2. Ashby J. (1997). Identifying potential human carcinogens-the role of genetically altered rodents. Toxicol Pathol, 25, 241-3.
3. Aylor DL, Valdar W, Foulds-Mathes W, et al. (2011). Genetic analysis of complex traits in the emerging Collaborative Cross. Genome Res, 21, 1213-22.
4. Berger AH, Knudson AG, Pandolfi PP. (2011). A continuum model for tumour suppression. Nature, 476, 163-9.
5. Blain PG, Battershill JM, Venitt S, et al. (1998). Consideration of shortterm carcinogenicity tests using transgenic mouse models. Mutat Res, 403, 259-63.
6. Boley SE, Anderson EE, French JE, et al. (2000). Loss of p53 in benzene-induced thymic lymphomas in p53?/- mice: Evidence of chromosomal recombination. Cancer Res, 60, 2831-5.
7. Boverhof DR, Chamberlain MP, Elcombe CR, et al. (2011). Transgenic animal models in toxicology: Historical perspectives and future outlook. Toxicol Sci, 121, 207-33.
8. Bucher JR. (1998). Update on national toxicology program (NTP) assays with genetically altered or transgenic mice. Environ Health Perspect, 106, 619-21.
9. Cannon RE, Graves S, Spalding JW, et al. (2000). Oral administration of dimethylvinyl chloride increases frequency of forestomach papillomas in Tg.AC mice. Mol Carcinog, 29, 229-35.
10. Carmichael NG, Debruyne EL, Bigot-Lasserre D. (2000). The p53 heterozygous knockout mouse as a model for chemical carcinogenesis in vascular tissue. Environ Health Perspect, 108, 61-5.
11. Carmichael PL, Mills JJ, Campbell M, et al. (2001). Mechanisms of hormonal carcinogenesis in the p53?/- hemizygous knockout mouse: Studies with diethylstilbestrol. Toxicol Pathol, 29, 155-60.
12. Castrop H. (2010). Genetically modified mice-successes and failures of a widely used technology. Pflugers Arch, 459, 557-67.
13. Chesler EJ, Miller DR, Branstetter LR, et al. (2008). The Collaborative Cross at Oak Ridge National Laboratory: developing a powerful resource for systems genetics. Mamm Genome, 19, 382-9.
14. Churchill GA, Airey DC, Allayee H, et al. (2004). The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nat Genet, 36, 1133-7.
15. Clarke AR. (2000). Manipulating the germline: Its impact on the study of carcinogenesis. Carcinogenesis, 21, 435-41.
16. Cohen SM, Robinson D, MacDonald J. (2001). Alternative models for carcinogenicity testing. Toxicol Sci, 64, 14-19.
17. Contrera JF, DeGeorge JJ. (1998). In vivo transgenic bioassays and assessment of the carcinogenic potential of pharmaceuticals. Environ Health Perspect, 106, 71-80.
18. Contrera JF, Jacobs AC, DeGeorge JJ. (1997). Carcinogenicity testing and the evaluation of regulatory requirements for pharmaceuticals. Regul Toxicol Pharmacol, 25, 130-45.
19. Dass SB, Bucci TJ, Heflich RH, Casciano DA. (1999). Evaluation of the transgenic p53?/- mouse for detecting genotoxic liver carcinogens in a short-term bioassay. Cancer Lett, 143, 81-5.
20. Dobrovolsky VN, Shaddock JG, Mittelstaedt RA, et al. (2007). Frequency of Hprt mutant lymphocytes and micronucleated erythrocytes in p53-haplodeficient mice treated perinatally with AZT and AZT in combination with 3TC. Environ Mol Mutagen, 48, 270-82.
21. Donehower LA. (1996). The p53-deficient mouse: A model for basic and applied cancer studies. Semin Cancer Biol, 7, 269-78.
22. Donehower LA, Harvey M, Slagle BL, et al. (1992). Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature, 356, 215-21.
23. Donehower LA, Lozano G. (2009). 20 years studying p53 functions in genetically engineered mice. Nat Rev Cancer, 9, 831-41.
24. Dunnick JK, Hardisty JF, Herbert RA, et al. (1997). Phenolphthalein induces thymic lymphomas accompanied by loss of the p53 wild type allele in heterozygous p53-deficient (?/-) mice. Toxicol Pathol, 25, 533-40.
25. Dunson DB, Haseman JK, van Birgelen AP, et al. (2000). Statistical analysis of skin tumor data from Tg.AC mouse bioassays. Toxicol Sci, 55, 293-302.
26. Eastin WC, Haseman JK, Mahler JF, Bucher JR. (1998). The National Toxicology Program evaluation of genetically altered mice as predictive models for identifying carcinogens. Toxicol Pathol, 26, 461-73.
27. Enzmann H, Iatropoulos M, Brunnemann KD, et al. (1998). Short- and intermediate-term carcinogenicity testing-a review. Part 2: Available experimental models. Food Chem Toxicol, 36, 997-1013.
28. Fearon ER, Vogelstein B. (1990). A genetic model for colorectal tumorigenesis. Cell, 61, 759-67.
29. Finch GL, March TH, Hahn FF, et al. (1998). Carcinogenic responses of transgenic heterozygous p53 knockout mice to inhaled 239PuO2 or metallic beryllium. Toxicol Pathol, 26, 484-91.
30. Forster R. (1998). A global collaboration on carcinogenicity screening in transgenic mouse models. Transgenic Res, 7, 485-7.
31. French J, Storer RD, Donehower LA. (2001a). The nature of the heterozygous Trp53 knockout model for identification of mutagenic carcinogens. Toxicol Pathol, 29, 24-9.
32. French JE, Lacks GD, Trempus C, et al. (2001b). Loss of heterozygosity frequency at the Trp53 locus in p53-deficient (?/-) mouse tumors is carcinogen-and tissue-dependent. Carcinogenesis, 22, 99-106.
33. French JE, Leblanc B, Long GG, et al. (2010). Panel discussion: Alternative mouse models for carcinogenicity assessment. Toxicol Pathol, 38, 72-5.
34. Furst SM, Stoll RE, Mennear J. (2000). Dermal carcinogenicity in transgenic mice: Effect of vehicle on responsiveness of hemizygous Tg.AC mice to phorbol ester (TPA). The Tg.AC Workgroup Newsletter, 3, 1-2.
35. Gold LS, Bernstein L, Magaw R, Slone TH. (1989). Interspecies extrapolation in carcinogenesis: prediction between rats and mice. Environ Health Perspect, 81, 211-19.
36. Goldsworthy TL, Recio L, Brown K, et al. (1994). Transgenic animals in toxicology. Fundam Appl Toxicol, 22, 8-19.
37. Gollapudi BB, Stott WT, Yano BL, Bus JS. (1998). Mode of action considerations in the use of transgenic animals for mutagenicity and carcinogenicity evaluations. Toxicol Lett, 102-103, 479-84.
38. Gonzalez FJ. (2001). The use of gene knockout mice to unravel the mechanisms of toxicity and chemical carcinogenesis. Toxicol Lett, 120, 199-208.
39. Gonzalez FJ. (2003). Role of gene knockout and transgenic mice in the study of xenobiotic metabolism. Drug Metab Rev, 35, 319-35.
40. Goodman JI. (2001). A perspective on current and future uses of alternative models for carcinogenicity testing. Toxicol Pathol, 29, 173-6.
41. Gray GM, Li P, Shlyakhter I, Wilson R. (1995). An empirical examination of factors influencing prediction of carcinogenic hazard across species. Regul Toxicol Pharmacol, 22, 283-91.
42. Gulezian D, Jacobson-Kram D, McCullough CB, et al. (2000). Use of transgenic animals for carcinogenicity testing: Considerations and implications for risk assessment. Toxicol Pathol, 28, 482-99.
43. Healy LN, Pluta LJ, James RA, et al. (2001). Induction and timedependent accumulation of micronuclei in peripheral blood of transgenic p53?/- mice, Tg.AC (v-Ha-ras) and parental wild-type (C57BL/6 and FVB/N) mice exposed to benzene by inhalation. Mutagenesis, 16, 163-8.
44. Holden HE, Stoll RE, Spalding JW, Tennant RW. (1998). Hemizygous Tg.AC transgenic mouse as a potential alternative to the two-year mouse carcinogenicity bioassay: Evaluation of husbandry and housing factors. J Appl Toxicol, 18, 19-24.
45. Honchel R, Rosenzweig BA, Thompson KL, et al. (2001). Loss of palindromic symmetry in Tg.AC mice with a nonresponder phenotype. Mol Carcinog, 30, 99-110.
46. Huff J. (1999). Value, validity, and historical development of carcinogenesis studies for predicting and confirming carcinogenic risks to humans. In: Kitchin KT, ed. Carcinogenicity: Testing, predicting, and interpreting chemical effects. New York: Marcel Dekker, pp. 21-123.
47. Hulla JE, French JE, Dunnick JK. (2001). Chromosome 11 allelotypes reflect a mechanism of chemical carcinogenesis in heterozygous p53- deficient mice. Carcinogenesis, 22, 89-98.
48. Humble MC, Trempus CS, Spalding JW, et al. (2005). Biological, cellular, and molecular characteristics of an inducible transgenic skin tumor model: A review. Oncogene, 24, 8217-28.
49. Hunter KW (2012). Mouse models of cancer: does the strain matter? Nat Rev Cancer, 12, 144-9.
50. IARC. (1992). Mechanisms of carcinogenesis in risk identification. IARC Working Group Meeting; 1991 June 11-18; Lyon: IARC Sci Publ, pp. 1-608.
51. IARC. (1999). Consensus report. In: McGregor DB, Rice JM, Venitt S eds. The use of short- and medium-term tests for carcinogens and data on genetic effects in carcinogenic hazard evaluation. IARC Sci Publ, 146, 1-18.
52. IARC. (2000). Phenolphthalein. IARC Monographs on the Evaluation of Carcinogenic Risks to Man, 76, 387-415.
53. ICH.(1997). Guidance for Industry S1B Testing for Carcinogencity of Pharmaceuticals, International Conference on Harmonization, Expert Working Group on Safety, Geneva, Switzerland [Online]. Available from http://www. fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/ ucm074916.pdf [last accessed 23 Jul 2013]
54. Ito N, Shirai T, Hasegawa R. (1992). Medium-term bioassays for carcinogens. IARC Sci Publ, 116, 353-88.
55. Jacobs A. (2005). Prediction of 2-year carcinogenicity study results for pharmaceutical products: How are we doing? Toxicol Sci, 88, 18-23.
56. Jacobson-Kram D (2010). Cancer risk assessment approaches at the FDA/CDER: Is the era of the 2-year bioassay drawing to a close? Toxicol Pathol, 38, 169-70.
57. Jacobson-Kram D, Sistare FD, Jacobs AC. (2004). Use of transgenic mice in carcinogenicity hazard assessment. Toxicol Pathol, 32, 49-52.
58. Jaworski M, Hailfinger S, Buchmann A, et al. (2005). Human p53 knockin (hupki) mice do not differ in liver tumor response from their counterparts with murine p53. Carcinogenesis, 26, 1829-34.
59. Jerry DJ, Butel JS, Donehower LA, et al. (1994). Infrequent p53 mutations in 7,12-dimethylbenz[a]anthracene-induced mammary tumors in BALB/c and p53 hemizygous mice. Mol Carcinog, 9, 175-83.
60. Johnson FM. (1999). Carcinogenic chemical-response fingerprint for male F344 rats exposed to a series of 195 chemicals: Implications for predicting carcinogens with transgenic models. Environ Mol Mutagen, 34, 234-45.
61. Kawasaki Y, Hirabayashi Y, Kaneko T, et al. (2009). Benzene-induced hematopoietic neoplasms including myeloid leukemia in Trp53- deficient C57BL/6 and C3H/He mice. Toxicol Sci, 110, 293-306.
62. Kemp CJ. (1995). Hepatocarcinogenesis in p53-deficient mice. Mol Carcinog, 12, 132-6.
63. Leder A, Kuo A, Cardiff RD, et al. (1990). v-Ha-ras transgene abrogates the initiation step in mouse skin tumorigenesis: Effects of phorbol esters and retinoic acid. Proc Natl Acad Sci USA, 87, 9178-82.
64. Luo JL, Yang Q, Tong WM, et al. (2001). Knock-in mice with a chimeric human/murine p53 gene develop normally and show wild-type p53 responses to DNA damaging agents: A new biomedical research tool. Oncogene, 20, 320-8.
65. Lynch D, Svoboda J, Putta S. (2007). Mouse skin models for carcinogenic hazard identification: Utilities and challenges. Toxicol Pathol, 35, 853-64.
66. Macleod KF, Jacks T. (1999). Insights into cancer from transgenic mouse models. J Pathol, 187, 43-60.
67. Mahler JF, Flagler ND, Malarkey DE, et al. (1998). Spontaneous and chemically induced proliferative lesions in Tg.AC transgenic and p53-heterozygous mice. Toxicol Pathol, 26, 501-1.
68. Malumbres M, Barbacid M. (2003). RAS oncogenes: The first 30 years. Nat Rev Cancer, 3, 459-65.
69. Maronpot RR, Mitsumori K, Mann P, et al. (2000). Interlaboratory comparison of the CB6F1-Tg rasH2 rapid carcinogenicity testing model. Toxicology, 146, 149-59.
70. Marsella JM, Liu BL, Vaslet CA, Kane AB. (1997). Susceptibility of p53-deficient mice to induction of mesothelioma by crocidolite asbestos fibers. Environ Health Perspect, 105, 1069-72.
71. Medina D, Ullrich R, Meyn R, et al. (2002). Environmental carcinogens and p53 tumor-suppressor gene interactions in a transgenic mouse model for mammary carcinogenesis. Environ Mol Mutagen, 39, 178-83.
72. Menendez D, Inga A, Resnick MA. (2009). The expanding universe of p53 targets. Nat Rev Cancer, 9, 724-37.
73. Mitsumori K, Koizumi H, Nomura T, Yamamoto S. (1998). Pathological features of spontaneous and induced tumors in transgenic mice carrying a human prototype c-Ha-ras gene used for six-month carcinogenicity studies. Toxicol Pathol, 26, 520-31.
74. Mitsumori K, Wakana S, Yamamoto S, et al. (1997). Susceptibility of transgenic mice carrying human prototype c-Ha-ras gene in a shortterm carcinogenicity study of vinyl carbamate and ras gene analyses of the induced tumors. Mol Carcinog, 20, 298-307.
75. Nambiar PR, Turnquist SE, Morton D. (2012). Spontaneous tumor incidence in rasH2 mice: Review of internal data and published literature. Toxicol Pathol, 40, 614-23.
76. NCI. (1978). Bioassay of p-cresidine for possible carcinogenicity. Bethesda, MD: National Cancer Institute, Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health.
77. NCI. (1979). Bioassay of 2,4-diaminotoluene for possible carcinogenicity. Natl Cancer Inst Carcinog Tech Rep Ser, 162, 1-139.
78. NIEHS. (1997). Validation and Regulatory Acceptance. A Report of the ad hoc Interagency Coordinating Committee on the Validation of Alternative Methods, Research Triangle Park, NC. Available from: Http://iccvam.niehs.nih.gov/docs/ about-docs/validate.pdf [last accessed 23 Jul 2013].
79. NRC.(1983). Risk assessment in the federal government: Managing the process. Washington, D.C. National Research Council, National
80. Academy Press. NTP. (1979). Bioassay of p-cresidine for possible carcinogenicity. Natl Cancer Inst Carcinog Tech Rep Ser, 142, 1-123.
81. NTP. (1986). NTP toxicology and carcinogenesis studies of benzene (CAS No. 71-43-2) in F344/N rats and B6C3F1 mice (gavage studies). Natl Toxicol Program Tech Rep Ser, 289, 1-277.
82. NTP. (1987). NTP toxicology and carcinogenesis studies of bromodichloromethane (CAS No. 75-27-4) in F344/N rats and B6C3F1 mice (gavage studies). Natl Toxicol Program Tech Rep Ser, 321, 1-182.
83. NTP. (1989). Toxicology and carcinogenesis studies of 4-vinyl-1- cyclohexene diepoxide (CAS No. 106-87-6) in F344/N rats and B6C3F1 mice (dermal studies). Natl Toxicol Program Tech Rep Ser, 362, 1-249.
84. NTP. (1992). Toxicology and carcinogenesis studies of resorcinol (CAS No. 108-46-3) in F344 rats and B6C3F1 mice (gavage studies). Natl Toxicol Program Tech Rep Ser, 403, 1-234.
85. NTP. (1996). NTP toxicology and carcinogenesis studies of phenolphthalein (CAS No. 77-09-8) in F344/N rats and B6C3F1 mice (feed studies). Natl Toxicol Program Tech Rep Ser, 465, 1-354.
86. NTP. (2011) Twelfth Report on Carcinogens, Research Triangle Park, Available from: Http://ntp.niehs.nih.gov/?objectid=03C9AF75-E1BFFF40- DBA9EC0928DF8B15 [last accessed 23 Jul 2013].
87. NTP. (2004). Toxicology and carcinogensis. Studies of urethane, ethanol, and urethane/ethanol (urethane, CAS No. 51-79-6; ethanol, CAS No. 64-17-5) in B6C3F1 mice (drinking water studies). Natl Toxicol Program Tech Rep Ser, 510, 1-346.
88. NTP. (2006). NTP Toxicology and carcinogenesis studies of bromodichloromethane (CAS No. 75-27-4) in male F344/N rats and female B6C3F1 mice (drinking water studies). Natl Toxicol Program Tech Rep Ser, 532, 1-248.
89. NTP. (2007a). NTP report on the toxicology and carcinogenesis study of benzene (CAS No. 71-43-2) in genetically modified haploinsufficient p16 Ink4a/p19 Arf mice (gavage study). Natl Toxicol Program Genet Modif Model Rep, GMM 8, 1-81.
90. NTP. (2007b). Toxicology and carcinogenesis study of glycidol (CAS No. 556-52-5) in genetically modified haploinsufficient p16(Ink4a)/p19(Arf) mice (gavage study). Natl Toxicol Program Genet Modif Model Rep, GMM 13, 1-81.
91. NTP. (2007c). The toxicology and carcinogenesis study of phenolphthalein (CAS No. 77-09-8) in genetically modified haploinsufficient p16(Ink4a)/p19(Arf) mice (feed study). Natl Toxicol Program Genet Modif Model Rep, GMM 12, 1-85.
92. NTP. (2007d). Toxicology studies of bromodichloromethane (CAS No. 75-27-4) in genetically modified (FVB Tg.AC hemizygous) mice (dermal, drinking water, and gavage studies) and carcinogenicity studies of bromodichloromethane in genetically modified [B6.129- Trp53tm1Brd (N5) haploinsufficient] mice (drinking water and gavage studies). Natl Toxicol Program Genet Modif Model Rep, GMM 5, 1-227.
93. NTP. (2012a). NTP report on the toxicology and carcinogenicity study of mixtures of 3?-azido-3?-deoxythymidine (AZT), lamivudine (3TC), and nevirapine (NVP) (CAS NOS. 30516-87-1, 134678-17-4, 129618- 40-2) in genetically modified C3B6.129F1-Trp53tm1Brd N12 haploinsufficient mice (In utero and postnatal gavage study) draft. Natl Toxicol Program Genet Modif Model Rep GMM, 16, 1-260.
94. NTP. (2012b). Toxicology study of Senna (CAS No. 8013-11-4) in C57BL/6NTAC mice and toxicology and carcinogenesis study of senna in genetically modified C3B6.129F1/Tac-Trp53tm1Brd N12 haploinsufficient mice (Feed Studies). Natl Toxicol Program Genet Modif Model Rep, GMM 15, 1-114.
95. Nwosu VC, Kissling GE, Trempus CS, et al. (2004). Exposure of Tg.AC transgenic mice to benzene suppresses hematopoietic progenitor cells and alters gene expression in critical signaling pathways. Toxicol Appl Pharmacol, 196, 37-46.
96. Ozaki M, Ozaki K, Watanabe T, et al. (2005). Susceptibilities of p53 knockout and rasH2 transgenic mice to urethane-induced lung carcinogenesis are inherited from their original strains. Toxicol Pathol, 33, 267-71.
97. Pritchard JB, French JE, Davis BJ, Haseman JK. (2003). The role of transgenic mouse models in carcinogen identification. Environ Health Perspect, 111, 444-54.
98. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. (2011). RAS oncogenes: Weaving a tumorigenic web. Nat Rev Cancer, 11, 761-74.
99. Robinson DE, MacDonald JS. (2001). Background and framework for ILSI?s collaborative evaluation program on alternative models for carcinogenicity assessment. International Life Sciences Institute. Toxicol Pathol, 29, 13-19.
100. Rosenberg MP. (1997). Gene knockout and transgenic technologies in risk assessment: The next generation. Mol Carcinog, 20, 262-74.
101. Rudmann DG, Durham SK. (1999). Utilization of genetically altered animals in the pharmaceutical industry. Toxicol Pathol, 27, 111-14.
102. Saitoh A, Kimura M, Takahashi R, et al. (1990). Most tumors in transgenic mice with human c-Ha-ras gene contained somatically activated transgenes. Oncogene, 5, 1195-200.
103. Salleh MN, Ismail P, Abdullah AS, Taufiq-Yap YH. (2004). Gene expression profiling of p53(?/) knockout and wild-type mice following diethylstilbestrol administration. IUBMB Life, 56, 409-16.
104. Sanders JM, Burka LT, Chanas B, Matthews HB. (2001). Comparative xenobiotic metabolism between Tg.AC and p53?/ genetically altered mice and their respective wild types. Toxicol Sci, 61, 54-61.
105. Sgura A, De Amicis A, Stronati L, et al. (2008). Chromosome aberrations and telomere length modulation in bone marrow and spleen cells of melphalan-treated p53?/ mice. Environ Mol Mutagen, 49, 467-75.
106. Sills RC, French JE, Cunningham ML. (2001). New models for assessing carcinogenesis: An ongoing process. Toxicol Lett, 120, 187-98.
107. Spalding JW, French JE, Stasiewicz S, et al. (2000). Responses of transgenic mouse lines p53(?/) and Tg.AC to agents tested in conventional carcinogenicity bioassays. Toxicol Sci, 53, 213-23.
108. Spalding JW, French JE, Tice RR, et al. (1999). Development of a transgenic mouse model for carcinogenesis bioassays: Evaluation of chemically induced skin tumors in Tg.AC mice. Toxicol Sci, 49, 241-54.
109. Spalding JW, Momma J, Elwell MR, Tennant RW. (1993). Chemically induced skin carcinogenesis in a transgenic mouse line (TG.AC) carrying a v-Ha-ras gene. Carcinogenesis, 14, 1335-41.
110. Stoll RE, Furst SM, Stoltz JH, et al. (2001). Dermal carcinogenicity in transgenic mice: Effect of vehicle on responsiveness of hemizygous Tg.AC mice to phorbol 12-myristate 13-acetate (TPA). Toxicol Pathol, 29, 535-40.
111. Storer R. (1998). Experience to date with the positive control compounds p-cresidine and benzene. The p53 Workgroup Newsletter, 1, E7-8.
112. Storer RD, French JE, Haseman J, et al. (2001). P53?/- hemizygous knockout mouse: Overview of available data. Toxicol Pathol, 29, 30-50.
113. Storer RD, Sistare FD, Reddy MV, DeGeorge JJ. (2010). An industry perspective on the utility of short-term carcinogenicity testing in transgenic mice in pharmaceutical development. Toxicol Pathol, 38, 51-61.
114. Svenson KL, Gatti DM, Valdar W, et al. (2012). High-resolution genetic mapping using the Mouse Diversity outbred population. Genetics, 190, 437-47.
115. Tennant RW. (1998). Evaluation and validation issues in the development of transgenic mouse carcinogenicity bioassays. Environ Health Perspect, 106, 473-6.
116. Tennant RW, Butterworth BE, Preston RJ. (1999a). Genetically engineered cancer models: Three viewpoints on issues from testing to risk assessment. CIIT Activities, 19, 1-7.
117. 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, 942-50.
118. Tennant RW, Spalding J, French JE. (1996). Evaluation of transgenic mouse bioassays for identifying carcinogens and noncarcinogens. Mutat Res, 365, 119-27.
119. Tennant RW, Stasiewicz S, Eastin WC, et al. (2001). The Tg.AC (v-Haras) transgenic mouse: Nature of the model. Toxicol Pathol, 29, 51-9.
120. Tennant RW, Stasiewicz S, Mennear J, et al. (1999b). Genetically altered mouse models for identifying carcinogens. IARC Sci Publ, 146, 123-50.
121. Thompson KL, Rosenzweig BA, Sistare FD. (1998). An evaluation of the hemizygous transgenic Tg.AC mouse for carcinogenicity testing of pharmaceuticals. II. A genotypic marker that predicts tumorigenic responsiveness. Toxicol Pathol, 26, 548-55.
122. Threadgill DW, Miller DR, Churchill GA, de Villena FP. (2011). The collaborative cross: A recombinant inbred mouse population for the systems genetic era. ILAR J, 52, 24-31.
123. Travis CC. (1993). Interspecies extrapolation of toxicological data. In: Wang RGM, Knaak JB, Maibach HI eds. Health risk assessment: dermal and inhalation exposure and absorption of toxicants, Boca Raton: CRC Press, pp. 387-410.
124. Tsuda H, Fukamachi K, Ohshima Y, et al. (2005). High susceptibility of human c-Ha-ras proto-oncogene transgenic rats to carcinogenesis: A cancer-prone animal model. Cancer Sci, 96, 309-16.
125. U.S. EPA. (2011). Recommended Use of Body Weightg at the Default Method in Derivation of the Oral Reference Dose. Washington, DC. Office of Science Advisor; EPA/100/R11/0001, Available from: Http://www.epa.gov/raf/publications/ pdfs/recommended-use-of-bw34.pdf [last accessed 23 Jul 2013].
126. Urano K, Tamaoki N, Nomura T. (2012). Establishing a laboratory animal model from a transgenic animal: RasH2 mice as a model for carcinogenicity studies in regulatory science. Vet Pathol, 49, 16-23.
127. Valentine JL, Lee SS, Seaton MJ, et al. (1996). Reduction of benzene metabolism and toxicity in mice that lack CYP2E1 expression. Toxicol Appl Pharmacol, 141, 205-13.
128. van Boxtel R, Cuppen E. (2011). Generation of genetically modified rodents using random ENU mutagenesis. Methods Mol Biol, 693, 295-308.
129. van der Laan JW. (2000). Current status and use of short/medium-term models for assessment of carcinogenicity of human pharmaceuticals: Regulatory perspectives. Toxicol Lett, 112-113, 567-72.
130. van Kreijl CF, McAnulty PA, Beems RB, et al. (2001). Xpa and Xpa/p53?/- knockout mice: Overview of available data. Toxicol Pathol, 29, 117-27.
131. van Kreijl CF, van Steeg H. (1998). Transgenic mouse models for the identification of human carcinogens: A European perspective. Toxicol Pathol, 26, 757-8.
132. van Steeg H, de Vries A, van Oostrom C, et al. (2001). DNA repairdeficient Xpa and Xpa/p53?/- knock-out mice: Nature of the models. Toxicol Pathol, 29, 109-16.
133. Van Zeller A-M, Combes RD. (1999). Transgenic mouse bioassays for carcinogenicity testing: A step in the right direction? ATLA, 27, 839-46.
134. Venkatachalam S, Shi YP, Jones SN, et al. (1998). Retention of wild-type p53 in tumors from p53 heterozygous mice: Reduction of p53 dosage can promote cancer formation. EMBO J, 17, 4657-67.
135. Venkatachalam S, Tyner SD, Pickering CR, et al. (2001). Is p53 haploinsufficient for tumor suppression? Implications for the p53?/- mouse model in carcinogenicity testing. Toxicol Pathol, 29, 147-54.
136. Weaver JL, Contrera JF, Rosenzweig BA, et al. (1998). An evaluation of the hemizygous transgenic Tg.AC mouse for carcinogenicity testing of pharmaceuticals. I. Evidence for a confounding nonresponder phenotype. Toxicol Pathol, 26, 532-40.
137. Wells MY, Williams ES. (2009). The transgenic mouse assay as an alternative test method for regulatory carcinogenicity studies-implications for REACH. Regul Toxicol Pharmacol, 53, 150-5.
138. Yamamoto S, Urano K, Koizumi H, et al. (1998a). Validation of transgenic mice carrying the human prototype c-Ha-ras gene as a bioassay model for rapid carcinogenicity testing. Environ Health Perspect, 106 (Suppl. 1), 57-69.
139. Yamamoto S, Urano K, Nomura T. (1998b). Validation of transgenic mice harboring the human prototype c-Ha-ras gene as a bioassay model for rapid carcinogenicity testing. Toxicol Lett, 102-103, 473-8.
140. Yan HX, Wu HP, Ashton C et al. (2012). Rats deficient for p53 are susceptible to spontaneous and carcinogen-induced tumorigenesis. Carcinogenesis, 33, 2001-5.