Alternatives to the carcinogenicity bioassay for toxicity prediction: Are we there yet?

Expert Opinion on Drug Metabolism and Toxicology

Volumn 8, Issue 4, 2012, Pages 407-417

  Benigni, Romualdo ^a  

^a ISTITUTO SUPERIORE DI SANITÀ   (Italy)

Author keywords

Alternative; Carcinogenicity; DNA reactive; Genotoxicity; Human health; Mutagenicity; Nongenotoxic; Testing strategy

Indexed keywords

CARCINOGEN; MICRORNA;

BIOASSAY; CANCER CELL; CANCER RESEARCH; CANCER STEM CELL; CARCINOGEN DNA INTERACTION; CARCINOGENICITY; CELL STRAIN 3T3; CELL TRANSFORMATION; DNA METHYLATION; DNA STRUCTURE; ERYTHROCYTE; ESCHERICHIA COLI; GENETIC DAMAGE; GENETIC SCREENING; GENETIC TOXICOLOGY; GENOTOXICITY; HEART FAILURE; HIGH THROUGHPUT SCREENING; HUMAN; HYPOTHESIS; IN VITRO STUDY; IN VIVO STUDY; LIVER TOXICITY; MUTAGEN TESTING; MUTAGENICITY; NONHUMAN; PREDICTION; REVIEW; SALMONELLA TYPHIMURIUM; SENSITIVITY AND SPECIFICITY; SOMATIC CELL; STRUCTURE ACTIVITY RELATION;

ANIMAL TESTING ALTERNATIVES; ANIMALS; BIOLOGICAL ASSAY; CARCINOGENICITY TESTS; CARCINOGENS; CELL TRANSFORMATION, NEOPLASTIC; DNA; DRUG EVALUATION, PRECLINICAL; HUMANS; MICE; MUTAGENICITY TESTS; MUTAGENS; PHARMACEUTICAL PREPARATIONS; PREDICTIVE VALUE OF TESTS; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

ANIMALIA; SALMONELLA;

EID: 84858843662     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2012.666238     Document Type: Review

References (99)

1. Frankish H. 15 million new cancer cases per year by 2020, says WHO. Lancet 2003;361:1278
2. Tomatis L, Huff J, Hertz-Picciotto I, et al. Avoided and avoidable risks of cancer. Carcinogenesis 1997;18:97-105 . Convincing presentation on the predominant environmental origin of cancer and on how to reduce its incidence.
3. Sokal RR, Oden NL, Rosenberg MS, et al. Cancer incidences in Europe related to mortalities, and ethnohistoric, genetic, and geographic distances. Proc Natl Acad Sci USA 2000;97:6067-72
4. Belpomme D, Irigaray P, Sasco AJ, et al. The growing incidence of cancer: Role of lifestyle and screening detection. Int J Oncol 2007;30:1037-49
5. Belpomme D, Irigaray P, Hardell L, et al. The multitude and diversity of environmental carcinogens. Environ Res 2007;105:414-29
6. Liechtenstein P, Holm NV, Verkasalo PK, et al. Environmental and heritable factors in the causation of cancer. N Engl J Med 2000;343:78-84
7. Benigni R. Social sexual inequality, and sex difference in cancer incidence. Environ Res 2007;104:128-34
8. Benigni R, Bossa C. Mechanisms of chemical carcinogenicity and mutagenicity: A review with implications for predictive toxicology. Chem Rev 2011;111:2507-36 A review on the mechanisms of chemical carcinogenicity and on predictive toxicology through (Q)SAR.
9. Woo YT. Mechanisms of action of chemical carcinogens, and their role in Structure-Activity Relationships (SAR) analysis and risk assessment. In: Benigni R, editor. Quantitative Structure-Activity Relationship (QSAR) Models of Mutagens and Carcinogens. CRC Press; Boca Raton: 2003. p. 41-80 . Mechanistic presentation on chemical carcinogenicity, particularly rich on nongenotoxic carcinogens.
10. Miller EC, Miller JA. Mechanisms of chemical carcinogenesis. Cancer 1981;47:1055-64
11. Arcos JC, Argus MF, Woo YT. Chemical Induction of Cancer, Modulation and Combination Effects: An Inventory of the Many Factors which Influence Carcinogenesis. Birkhauser; Boston: 1995
12. Bartsch H. DNA adducts in human carcinogenesis: Etiological relevance and structure-activity relationship. Mutat Res 1996;340:67-9
13. Baker SG, Cappuccio A, Potter JD. Research on early-stage carcinogenesis: Are we approaching paradigm instability? J Clin Oncol 2010;28:3215-18 . A clear picture of the different theories on the early steps of carcinogenicity.
14. Hernandez LG, van Steeg H, Luijten M, et al. Mechanisms of non-genotoxic carcinogens and importance of a weight of evidence approach. Mutat Res 2009;682:94-109 . Informative and propositive on the regulatory implications of nongenotoxic carcinogens.
15. Melnick RL, Kohn MC, Portier CJ. Implications for risk assessment of suggested nongenotoxic mechanisms of chemical carcinogenesis. Environ Health Perspect 1996;104:123-34
16. Haseman JK, Melnick RL, Tomatis L, et al. Carcinogenesis bioassays: Study duration and biological relevance. Food Chem Toxicol 2001;39:739-44
17. Tomatis L, Melnick RL, Haseman JK, et al. Alleged " misconceptions" distort perceptions of environmental cancer risks. FASEB J 2001;15:195-203
18. Bucher JR. Doses in rodent cancer studies: Sorting fact from fiction. Drug Metab Rev 2000;32:153-63
19. Huff J. Long-term chemical carcinogenesis bioassays predict human cancer hazards. Issues, controversies, and uncertainties. Ann NY Acad Sci 1999;895:56-79 . The value of the rodent bioassay.
20. Huff J. Value, validity, and historical development of carcinogenesis studies for predicting and confirming carcinogenic risks to humans. In: Kitchin KT, editor. Carcinogenicity. Testing, predicting, and interpreting chemical effects. Marcel Dekker, Inc.; New York: 1999. p. 21-123
21. Fung VA, Huff J, Weisburger EK, et al. Predictive strategies for selecting 379 NCI/NTP chemicals evaluated for carcinogenic potential: Scientific and public health impact. Fund Appl Toxicol 1993;20:413-36
22. Huff JE, Haseman JK, Rall DP. Scientific concepts, value, and significance of chemical carcinogenesis studies. Ann Rev Pharmacol Toxicol 1991;31:621-5
23. Allen BC, Crump KS, Shipp AM. Correlation between carcinogenic potency of chemicals in animals and humans. Risk Anal 1988;8:531-44
24. Goodman G, Wilson R. Quantitative prediction of human cancer risk from rodent carcinogenic potencies: A closer look at the epidemiological evidence for some chemicals not definitively carcinogenic in humans. Regul Pharmacol Toxicol 1991;14:118-46
25. Tomatis L. Identification of carcinogenic agents and primary prevention of cancer. Ann NY Acad Sci 2006;1076:1-14
26. Tomatis L. Primary prevention of cancer in relation to science, sociocultural trends and economic pressures. Scand J Work Environ Health 2005;31:165-7
27. Huff J. Primary prevention of cancer. Science 2011;331:1539
28. Kaufman JS. Progress and pitfalls in the social epidemiology of cancer. Cancer Causes Control 1999;10:489-94
29. Taubes G. Epidemiology faces its limits. Science 1995;269:164-9
30. Worth AP. The role of QSAR methodology in the regulatory assessment of chemicals. In: Puzyn T, Leszczynski J, Cronin MTD, editors. Recent Advances in QSAR Studies: Methods and Applications. Springer; Heidelberg: 2010. p. 367-82
31. Worth AP, Bassan A, de Brujin J, et al. The Role of the European chemicals Bureau in promoting the regulatory use of (Q)SAR methods. SAR QSAR Environ Res 2007;18:111-25
32. European Commission. Proposal concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH). COM(2003) 644Final. 2003
33. Hansch C, Kim D, Leo AJ, et al. Toward a quantitative comparative toxicology of organic compounds. Crit Rev Toxicol 1989;19:185-226 Introduction to a high-level use and comprehension of QSAR.
34. Van Leeuwen K, Schultz TW, Henry T, et al. Using chemical categories to fill data gaps in hazard assessment. SAR QSAR Environ Res 2009;20:207-20
35. Benigni R, Netzeva TI, Benfenati E, et al. The expanding role of predictive toxicology: An update on the (Q)SAR models for mutagens and carcinogens. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2007;25:53-97
36. Tsuda H, Futakuchi M, Fukamachi K, et al. A medium-term, rapid rat bioassay model for the detection of carcinogenic potential of chemicals. Toxicol Pathol 2010;38:182-7
37. Haseman JK, Huff JE. Species correlation in long-term carcinogenicity studies. Cancer Lett 1987;37:125-32
38. Wunderlich V. Early references to the mutational origin of cancer. Int J Epidemiol 2007;36:246-7
39. Haber DA, Settleman J. Cancer: Drivers and passengers. Natur 2007;446:145-6
40. Soto AM, Sonnenschein C. The tissue organization field theory of cancer: A testable replacement for the somatic mutation theory. Bioessays 2011;33:332-40
41. Potter JD. Morphostats, morphogens, microarchitecture and malignancy. Nat Rev Cancer 2007;7:464-74
42. Chouroulinkov I. Initiation, promotion: Working concepts, biological and toxicological interpretations of carcinogenesis. In: Iversen OH, editor. Theories of Carcinogenesis. Hemisphere Publishing Co.; Washington, DC: 1988. p. 191-201
43. Yamasaki H, Mesnil M, Nakazawa H. Interaction and distinction of genotoxic and non-genotoxic events in carcinogenesis. Toxicol Lett 1992;64-65:597-604
44. Zeiger E. History and rationale of genetic toxicity testing: An impersonal, and sometimes personal, view. Environ Mol Mutagen 2004;44:363-71 An overall picture of genetic toxicology.
45. Mortelmans K, Zeiger E. The ames salmonella/microsome mutagenicity assay. Mutat Res 2000;455:29-60
46. Ashby J. Fundamental structural alerts to potential carcinogenicity or noncarcinogenicity. Environ Mutagen 1985;7:919-21
47. Zeiger E. Strategies and philosophies of genotoxicity testing: What is the question? Mutat Res 1994;304:309-14
48. ICH. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Guidance on genotoxicity testing and data interpretation for pharmaceuticals intended for human use. S2(R1). 2008
49. Kirkland D, Speit G. Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens III. Appropriate follow-up testing in vivo. Mutat Res 2008;654:114-32
50. Elespuru RK, Agarwal R, Atrakchi AH, et al. Current and future application of genetic toxicity assays: The role and value of in vitro mammalian assays. Toxicol Sci 2009;109:172-9
51. EFSA. Scientific opinion on genotoxicity testing strategies applicable to food and feed safety assessment. EFSA J 2011;9:2379
52. Kirkland D, Aardema MJ, Henderson L, et al. Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens I. Sensitivity, specificity and relative predictivity. Mutat Res 2005;584:1-256
53. Zeiger E. Identification of rodent carcinogens and noncarcinogens using genetic toxicity tests: Premises, promises, and performance. Regul Pharmacol Toxicol 1998;28:85-95 Opinions and facts on genetic toxicology.
54. Benigni R, Bossa C, Tcheremenskaia O, et al. Alternatives to the carcinogenicity bioassay: In silico methods, and the in vitro and in vivo mutagenicity assays. Expert Opin Drug Metab Toxicol 2010;6:1-11
55. Benigni R, Bossa C, Tcheremenskaia O, et al. The new ISSMIC database on in vivo micronucleus, and its role in assessing genotoxicity testing strategies. Mutagenesis 2012;27:87-92
56. Pedersen F, de Brujin J, Munn SJ, Van Leeuwen K. Assessment of additional testing needs under REACH. Effects of (Q)SARs, risk based testing and voluntary industry initiatives. JRC report EUR 20863 EN. 2003. Ispra, EU.R.
57. Van der Jagt K, Munn SJ, Torslov J, de Brujin J. Alternative approaches can reduce the use of test animals under REACH. Addendum to the Report "Assessment of addtional testing needs under REACH. Effects of (Q)SARs, risk based testing and voluntary industry initiatives". JRC Report EUR 21405 EN. 2004. Ispra, European Commission Joint Research Centre
58. Leopardi P, Cordelli E, Villani P, et al. Assessment of in vivo genotoxicity of the rodent carcinogen furan: Evaluation of DNA damage and induction of micronuclei in mouse splenocytes. Mutagenesis 2010;25:57-62
59. Cordelli E, Leopardi P, Villani P, et al. Toxic and genotoxic effects of oral administration of furan in mouse liver. Mutagenesis 2010;25:305-14
60. Huff J. More toxin tests needed. Science 2008;319:725-6
61. Kirkland D, Pfuhler S, Tweats D, et al. How to reduce false positive results when undertaking in vitro genotoxicity testing and thus avoid unnecessary follow-up animal tests: Report of an ECVAM workshop. Mutat Res 2007;628:31-55
62. Kirkland D, Kasper P, Muller L, et al. Recommended lists of genotoxic and non-genotoxic chemicals for assessment of the performance of new or improved genotoxicity tests: A follow-up to an ECVAM workshop. Mutat Res 2008;653:99-108
63. Benigni R, Bossa C, Giuliani A, et al. Exploring in vitro/in vivo correlations: Lessons learned from analyzing phase I results of U.S.EPA's ToxCast project. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2010;28:272-86
64. Barrett JC, Ts'o PO. Evidence for the progressive nature of neoplastic transformation in vitro. Proc Natl Acad Sci USA 1978;75:3761-5
65. Berwald Y, Sachs L. In vitro transformation of normal cells to tumour cells by carcinogenic hydrocarbons. J Natl Cancer Inst 1965;35:641-61
66. Berwald Y, Sachs L. In vitro cell transformation with chemical carcinogens. Natur 1963;200:1182-4
67. OECD. Detailed review paper on cell transformation assays for detection of chemical carcinogens. (31). 2007. Paris, OECD. OECD Series on Testing and Assessment. Theory, experimental data and evaluations on the cell transformation assays.
68. Vanparys P, Corvi R, Aardema M, et al. ECVAM prevalidation of three cell transformation assays. ALTEX 2010;27:267-70
69. Corvi R, Aardema MJ, Gribaldo L, et al. ECVAM prevalidation study on in vitro cell transformation assays: General outline and conclusions of the study. Mutat Res 2011; Epub ahead of print
70. Benigni R, Bossa C. Alternative strategies for carcinogenicity assessment: An efficient and simplified approach based on in vitro mutagenicity and cell transformation assays. Mutagenesis 2011;26:455-60
71. Takahashi M, Barrett JC, Tsustsui T. Transformation by inorganic arsenic compounds of normal Syrian hamster embryo cells into a neoplastic state in which they become anchorage-independent and cause tumors in newborn hamsters. Int J Cancer 2002;99:629-34
72. Benigni R, Giuliani A. Quantitative modeling and biology: The multivariate approach. Am J Physiol 1994;266:R1697-704
73. Creton S, Aardema MJ, Carmichael P, et al. Cell transformation assays for prediction of carcinogenic potential: State of the science and future research needs. Mutagenesis 2012;62:93-101
74. Mauthe RJ, Gibson DP, Bunch RT, et al. The syrian hamster embryo (SHE) cell transformation assay: Review of the methods and results. Toxicol Pathol 2001;29:138-46
75. Haga K, Ohno S, Yugawa T, et al. Efficient immortalization of primary human cells by p.16INK4a-specific short hairpin RNA or Bmi-1, combined with introduction of hTERT. Cancer Sci 2007;98:147-54
76. Duesberg P, Li R, Fabarius A, et al. The chromosomal basis of cancer. Cell Oncol 2005;27:293-318
77. Rowley JD. Chromosomes in leukemia and beyond: From irrelevant to central players. Annu Rev Genomics Hum Genet 2009;10:1-18
78. Young D. Drug innovation on the decline. Am J Health Syst Pharm 2009;64:228-31
79. Walters WP, Green J, Weiss JR, et al. What do medicinal chemists actually make? A 50-year retrospective. J Med Chem 2011;54:6405-16
80. Hopkins AL. Network pharmacology: The next paradigm in drug discovery. Nat Chem Biol 2008;4:682-90
81. MacDonald JS, Robertson RT. Toxicity testing in the 21st century: A view from the pharmaceutical industry. Toxicol Sci 2009;110:40-6
82. Benigni R, Bossa C. Structure alerts for carcinogenicity, and the salmonella assay system: A novel insight through the chemical relational databases technology. Mutat Res Rev 2008;659:248-61
83. Bignami M, Ficorella C, Dogliotti E, et al. Temporal dissociation in the exposure times required for maximal induction of cytotoxicity, mutation, and transformation by N-methyl-N'-nitro- N-nitrosoguanidine in the BALB/3T3 ClA31-1-1 cell line. Cancer Res 1984;44:2452-7
84. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer 2006;6:392-401
85. Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008;27:5904-12
86. Alcaraz J, Xu R, Mori H, et al. Laminin and biomimetic extracellular elasticity enhance functional differentiation in mammary epithelia. EMBO J 2008;27:2829-38
87. Ideaconsult ltd. Toxtree. Available from: Http://ihcp.jrc.ec.europa.eu/ our-labs/computational-toxicology/qsar-tools/toxtree-labs/computational- toxicology/qsar-tools/toxtree2.52.5 2011
88. Benigni R, Bossa C. Predictivity of QSAR. J Chem Inf Model 2008;48:971-80
89. Woo YT, Lai DY. Mechanism-based structure-activity relationship analysis of chemical carcinogens. In: Hsu G, Stedeford T, editors. Cancer Risk Assessment: Chemical Carcinogenesis, Hazard Evaluation, and Risk Quantification. Wiley; New York: 2010. p. 517-56
90. Benigni R. The second international collaborative study on comparative mutagenesis re-visited: Analysis by multivariate statistical methods. Mutagenesis 1986;1:185-90
91. Benigni R. Mutagenicity testing: New national toxicology program (NTP) data confirm old data but question old interpretations. Mutagenesis 1987;2:239-40
92. Zeiger E, Haseman JK, Shelby MD, et al. Evaluation of four in vitro genetic toxicity tests for predicting rodent carcinogenicity: Confirmation of earlier results with 41 additional chemicals. Environ Mol Mutagen 1990;16:1-14
93. Tennant RW, Margolin BH, Shelby MD, et al. Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays. Science 1987;236:933-41
94. Shelby MD, Erexson GL, Hook GJ, et al. Evalution of a three-exposure mouse bone marrow micronucleus protocol: Results with 49 chemicals. Environ Mol Mutagen 1993;21:160-79
95. Kavlock RJ, Austin CP, Tice RR. Toxicity testing in the 21st century: Implications for human health risk assessment. Risk Anal 2009;29:485-7
96. Ankley GT, Bennett RS, Erickson RJ, et al. Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem 2011;29:730-41
97. Elowitz MB, Levine AJ, Siggia ED, et al. Stochastic gene expression in a single cell. Science 2002;297:1183-6
98. ISSTOX databases cluster. Available from: Http://www.iss.it/ampp/dati/ cont. php?id=233&lang=1&tipo=7
99. Leadscope toxicity database. Available from: Http://www.leadscope.com/ toxicity-database/