713
Views
33
CrossRef citations to date
0
Altmetric
Review Articles

An integrative test strategy for cancer hazard identification

, , , , , & show all
Pages 615-639 | Received 23 Aug 2015, Accepted 23 Mar 2016, Published online: 03 May 2016

References

  • Aardema MJ, Barnett BB, Mun GC, Dahl EL, Curren RD, Hewitt NJ, Pfuhler S. 2013. Evaluation of chemicals requiring metabolic activation in the EpiDerm 3D human reconstructed skin micronucleus (RSMN) assay. Mutat Res. 750:40–49.
  • Accelrys DS TOPKAT Software. (2015). [cited 2015 April 7]. Available from: http://accelrys.com/products/datasheets/qsaradmet-and-predicitive-toxicology-with-ds.pdf.
  • Adler S, Basketter D, Creton S, Pelkonen O, van Benthem J, Zuang V, Andersen KE, Angers-Loustau A, Aptula A, Bal-Price A, et al. 2011. Alternative (non-animal) methods for cosmetics testing: current status and future prospects-2010. Arch Toxicol. 85:367–485.
  • Alison RH, Capen CC, Prentice DE. 1994. Neoplastic lesions of questionable significance to humans. Toxicol Pathol. 22:179–186.
  • Allen DG, Pearse G, Haseman JK, Maronpot RR. 2004. Prediction of rodent carcinogenesis: an evaluation of prechronic liver lesions as forecasters of liver tumors in NTP carcinogenicity studies. Toxicol Pathol. 32:393–401.
  • Ament Z, Waterman CL, West JA, Waterfield C, Currie RA, Wright J, Griffin JL. 2013. A metabolomics investigation of non-genotoxic carcinogenicity in the rat. J Proteome Res. 12:5775–5790.
  • Ames BN, Gold LS. 1990. Chemical carcinogenesis: too many rodent carcinogens. Proc Natl Acad Sci USA. 87:7772–7776.
  • Ankley GT, Bennett RS, Erickson RJ, Hoff DJ, Hornung MW, Johnson RD, Mount DR, Nichols JW, Russom CL, Schmieder PK, et al. 2010. Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem. 29:730–741.
  • Annys E, Billington R, Clayton R, Bremm KD, Graziano M, McKelvie J, Ragan I, Schwarz M, van der Laan JW, Wood C, et al. 2014. Advancing the 3Rs in regulatory toxicology – carcinogenicity testing: scope for harmonisation and advancing the 3Rs in regulated sectors of the European Union. Regul Toxicol Pharmacol. 69:234–242.
  • Armitage P, Doll R. 1954. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br J Cancer. 8:1–12.
  • Ashby J, Tennant RW. 1991. Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP. Mutat Res. 257:229–306.
  • Benigni R, Bossa C, Tcheremenskaia O. 2013. Nongenotoxic carcinogenicity of chemicals: mechanisms of action and early recognition through a new set of structural alerts. Chem Rev. 113:2940–2957.
  • Berenblum I, Shubik P. 1947. The role of croton oil applications, associated with a single painting of a carcinogen, in tumour induction of the mouse's skin. Br J Cancer. 1:379–382.
  • Bessems JG, Loizou G, Krishnan K, Clewell HJ 3rd, Bernasconi C, Bois F, Coecke S, Collnot EM, Diembeck W, Farcal LR, et al. 2014. PBTK modelling platforms and parameter estimation tools to enable animal-free risk assessment: recommendations from a joint EPAA–EURL ECVAM ADME workshop. Regul Toxicol Pharmacol. 68:119–139.
  • Beyer LA, Beck BD, Lewandowski TA. 2011. Historical perspective on the use of animal bioassays to predict carcinogenicity: evolution in design and recognition of utility. Crit Rev Toxicol. 41:321–338.
  • Billington R, Lewis RW, Mehta JM, Dewhurst I. 2010. The mouse carcinogenicity study is no longer a scientifically justifiable core data requirement for the safety assessment of pesticides. Crit Rev Toxicol. 40:35–49.
  • Billinton N, Bruce S, Hansen JR, Hastwell PW, Jagger C, McComb C, Klug ML, Pant K, Rabinowitz A, Rees R, et al. 2010. A pre-validation transferability study of the GreenScreen HC GADD45a-GFP assay with a metabolic activation system (S9). Mutat Res. 700:44–50.
  • Billinton N, Hastwell PW, Beerens D, Birrell L, Ellis P, Maskell S, Webster TW, Windebank S, Woestenborghs F, Lynch AM, et al. 2008. Interlaboratory assessment of the GreenScreen HC GADD45a-GFP genotoxicity screening assay: an enabling study for independent validation as an alternative method. Mutat Res. 653:23–33.
  • Birrell L, Cahill P, Hughes C, Tate M, Walmsley RM. 2010. GADD45a-GFP GreenScreen HC assay results for the ECVAM recommended lists of genotoxic and non-genotoxic chemicals for assessment of new genotoxicity tests. Mutat Res. 695:87–95.
  • Blaauboer BJ, Boekelheide K, Clewell HJ, Daneshian M, Dingemans MM, Goldberg AM, Heneweer M, Jaworska J, Kramer NI, Leist M, et al. 2012. The use of biomarkers of toxicity for integrating in vitro hazard estimates into risk assessment for humans. Altex. 29:411–425.
  • Boobis AR, Cohen SM, Dellarco V, McGregor D, Meek ME, Vickers C, Willcocks D, Farland W. 2006. IPCS framework for analyzing the relevance of a cancer mode of action for humans. Crit Rev Toxicol. 36:781–792.
  • Boobis AR, Cohen SM, Doerrer NG, Galloway SM, Haley PJ, Hard GC, Hess FG, Macdonald JS, Thibault S, Wolf DC, et al. 2009a. A data-based assessment of alternative strategies for identification of potential human cancer hazards. Toxicol Pathol. 37:714–732.
  • Boobis AR, Daston GP, Preston RJ, Olin SS. 2009b. Application of key events analysis to chemical carcinogens and noncarcinogens. Crit Rev Food Sci Nutr. 49:690–707.
  • Boobis AR, Doe JE, Heinrich-Hirsch B, Meek ME, Munn S, Ruchirawat M, Schlatter J, Seed J, Vickers C. 2008. IPCS framework for analyzing the relevance of a noncancer mode of action for humans. Crit Rev Toxicol. 38:87–96.
  • Bourcier T, McGovern T, Stavitskaya L, Kruhlak N, Jacobson-Kram D. 2015. Improving prediction of carcinogenicity to reduce, refine, and replace the use of experimental animals. J Am Assoc Lab Anim Sci. 54:163–169.
  • Boverhof DR, Chamberlain MP, Elcombe CR, Gonzalez FJ, Heflich RH, Hernandez LG, Jacobs AC, Jacobson-Kram D, Luijten M, Maggi A, et al. 2011. Transgenic animal models in toxicology: historical perspectives and future outlook. Toxicol Sci. 121:207–233.
  • Brendler-Schwaab S, Hartmann A, Pfuhler S, Speit G. 2005. The in vivo comet assay: use and status in genotoxicity testing. Mutagenesis. 20:245–254.
  • Brent RL. 2015. Protection of the gametes embryo/fetus from prenatal radiation exposure. Health Phys. 108:242–274.
  • Bryce SM, Avlasevich SL, Bemis JC, Tate M, Walmsley RM, Saad F, Van Dijck K, De Boeck M, Van Goethem F, Lukamowicz-Rajska M, et al. 2013. Flow cytometric 96-well microplate-based in vitro micronucleus assay with human TK6 cells: protocol optimization and transferability assessment. Environ Mol Mutagen. 54:180–194.
  • Buick JK, Moffat I, Williams A, Swartz CD, Recio L, Hyduke DR, Li HH, Fornace AJ, Jr., Aubrecht J, Yauk CL. 2015. Integration of metabolic activation with a predictive toxicogenomics signature to classify genotoxic versus nongenotoxic chemicals in human TK6 cells. Environ Mol Mutagen. 56:520–534.
  • Cao X, Mittelstaedt RA, Pearce MG, Allen BC, Soeteman-Hernandez LG, Johnson GE, Bigger CA, Heflich RH. 2014. Quantitative dose-response analysis of ethyl methanesulfonate genotoxicity in adult gpt-delta transgenic mice. Environ Mol Mutagen. 55:385–399.
  • Carmichael N, Bausen M, Boobis AR, Cohen SM, Embry M, Fruijtier-Polloth C, Greim H, Lewis R, Bette Meek ME, Mellor H, et al. 2011. Using mode of action information to improve regulatory decision-making: an ECETOC/ILSI RF/HESI workshop overview. Crit Rev Toxicol. 41:175–186.
  • Chapman KE, Thomas AD, Wills JW, Pfuhler S, Doak SH, Jenkins GJ. 2014. Automation and validation of micronucleus detection in the 3D EpiDerm™ human reconstructed skin assay and correlation with 2D dose responses. Mutagenesis. 29:165–175.
  • Clewell HJ, Gentry PR, Gearhart JM, Allen BC, Andersen ME. 2001. Comparison of cancer risk estimates for vinyl chloride using animal and human data with a PBPK model. Sci Total Environ. 274:37–66.
  • Clewell HJ, Tan YM, Campbell JL, Andersen ME. 2008. Quantitative interpretation of human biomonitoring data. Toxicol Appl Pharmacol. 231:122–133.
  • Clift MJ, Raemy DO, Endes C, Ali Z, Lehmann AD, Brandenberger C, Petri-Fink A, Wick P, Parak WJ, Gehr P, et al. 2013. Can the Ames test provide an insight into nano-object mutagenicity? Investigating the interaction between nano-objects and bacteria. Nanotoxicology. 7:1373–1385.
  • Coecke S, Pelkonen O, Leite SB, Bernauer U, Bessems JG, Bois FY, Gundert-Remy U, Loizou G, Testai E, Zaldivar JM. 2013. Toxicokinetics as a key to the integrated toxicity risk assessment based primarily on non-animal approaches. Toxicol In Vitro. 27:1570–1577.
  • Cohen SM. 1998. Cell proliferation and carcinogenesis. Drug Metab Rev. 30:339–357.
  • Cohen SM. 2004. Human carcinogenic risk evaluation: an alternative approach to the two-year rodent bioassay. Toxicol Sci. 80:225–229.
  • Cohen SM. 2010. Evaluation of possible carcinogenic risk to humans based on liver tumors in rodent assays: the two-year bioassay is no longer necessary. Toxicol Pathol. 38:487–501.
  • Cohen SM, Ellwein LB. 1991. Genetic errors, cell proliferation, and carcinogenesis. Cancer Res. 51:6493–6505.
  • Cohen SM, Klaunig J, Meek ME, Hill RN, Pastoor T, Lehman-McKeeman L, Bucher J, Longfellow DG, Seed J, Dellarco V, et al. 2004. Evaluating the human relevance of chemically induced animal tumors. Toxicol Sci. 78:181–186.
  • Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. 2009. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 30:1073–1081.
  • Dean SW, Brooks TM, Burlinson B, Mirsalis J, Myhr B, Recio L, Thybaud V. 1999. Transgenic mouse mutation assay systems can play an important role in regulatory mutagenicity testing in vivo for the detection of site-of-contact mutagens. Mutagenesis. 14:141–151.
  • Decordier I, Papine A, Vande Loock K, Plas G, Soussaline F, Kirsch-Volders M. 2011. Automated image analysis of micronuclei by IMSTAR for biomonitoring. Mutagenesis. 26:163–168.
  • DEREK Nexus. (2015). A knowledge based toxicity prediction tool; [cited 2015 April 7]. Available from: http://www.lhasalimited.org/products/derek-nexus.htm.
  • Dertinger SD, Phonethepswath S, Avlasevich SL, Torous DK, Mereness J, Bryce SM, Bemis JC, Bell S, Weller P, Macgregor JT. 2012. Efficient monitoring of in vivo pig-a gene mutation and chromosomal damage: summary of 7 published studies and results from 11 new reference compounds. Toxicol Sci. 130:328–348.
  • Doak SH, Manshian B, Jenkins GJ, Singh N. 2012. In vitro genotoxicity testing strategy for nanomaterials and the adaptation of current OECD guidelines. Mutat Res. 745:104–111.
  • Dobrovolsky VN, Miura D, Heflich RH, Dertinger SD. 2010. The in vivo Pig-a gene mutation assay, a potential tool for regulatory safety assessment. Environ Mol Mutagen. 51:825–835.
  • Eastin WC, Mennear JH, Tennant RW, Stoll RE, Branstetter DG, Bucher JR, McCullough B, Binder RL, Spalding JW, Mahler JF. 2001. Tg.AC genetically altered mouse: assay working group overview of available data. Toxicol Pathol. 29 Suppl:60–80.
  • Eastmond DA, Hartwig A, Anderson D, Anwar WA, Cimino MC, Dobrev I, Douglas GR, Nohmi T, Phillips DH, Vickers C. 2009. Mutagenicity testing for chemical risk assessment: update of the WHO/IPCS Harmonized Scheme. Mutagenesis. 24:341–349.
  • Eastmond DA, Vulimiri SV, French JE, Sonawane B. 2013. The use of genetically modified mice in cancer risk assessment: challenges and limitations. Crit Rev Toxicol. 43:611–631.
  • EC. (2008). Council Regulation (EC) No 440/2008 of 30 May 2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH). Official Journal L 142:1–739.
  • EC. (2009). Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products. Official Journal L 342:59–209.
  • EC. (2013). Commission Regulation (EU) No 284/2013 of 1 March 2013 setting out the data requirements for plant protection products, in accordance with Regulation (EC) No 1107/2009 of the European Parliament and of the Council concerning the placing of plant protection products on the market. Official Journal L 93:85–152.
  • ECHA. (2014). The Use of Alternatives to Testing on Animals for the REACH Regulation. Second report under Article 117(3) of the REACH Regulation. Available from: http://echa.europa.eu/documents/10162/13639/alternatives_test_animals_2014_en.pdf.
  • Elcombe CR, Odum J, Foster JR, Stone S, Hasmall S, Soames AR, Kimber I, Ashby J. 2002. Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens. Environ Health Perspect. 110:363–375.
  • Ellinger-Ziegelbauer H, Fostel JM, Aruga C, Bauer D, Boitier E, Deng S, Dickinson D, Le Fevre AC, Fornace AJ Jr, Grenet O, et al. 2009. Characterization and interlaboratory comparison of a gene expression signature for differentiating genotoxic mechanisms. Toxicol Sci. 110:341–352.
  • Ellinger-Ziegelbauer H, Gmuender H, Bandenburg A, Ahr HJ. 2008. Prediction of a carcinogenic potential of rat hepatocarcinogens using toxicogenomics analysis of short-term in vivo studies. Mutat Res. 637:23–39.
  • Ellinger-Ziegelbauer H, Stuart B, Wahle B, Bomann W, Ahr HJ. 2005. Comparison of the expression profiles induced by genotoxic and nongenotoxic carcinogens in rat liver. Mutat Res. 575:61–84.
  • EMA (European Medicines Agency). 2012. Guideline on the investigation of drug interactions. London: EMA.
  • Fearon ER, Vogelstein B. 1990. A genetic model for colorectal tumorigenesis. Cell. 61:759–767.
  • Fellows MD, O'Donovan MR. 2007. Cytotoxicity in cultured mammalian cells is a function of the method used to estimate it. Mutagenesis. 22:275–280.
  • Fielden MR, Adai A, Dunn RT, 2nd, Olaharski A, Searfoss G, Sina J, Aubrecht J, Boitier E, Nioi P, Auerbach S, et al. 2011. Development and evaluation of a genomic signature for the prediction and mechanistic assessment of nongenotoxic hepatocarcinogens in the rat. Toxicol Sci. 124:54–74.
  • Fielden MR, Brennan R, Gollub J. 2007. A gene expression biomarker provides early prediction and mechanistic assessment of hepatic tumor induction by nongenotoxic chemicals. Toxicol Sci. 99:90–100.
  • Fjodorova N, Vracko M, Novic M, Roncaglioni A, Benfenati E. 2010. New public QSAR model for carcinogenicity. Chem Cent J. 4:S3.
  • Fluckiger-Isler S, Kamber M. 2012. Direct comparison of the Ames microplate format (MPF) test in liquid medium with the standard Ames pre-incubation assay on agar plates by use of equivocal to weakly positive test compounds. Mutat Res. 747:36–45.
  • Foulds L. 1954. The experimental study of tumor progression: a review. Cancer Res. 14:327–339.
  • Fowler P, Smith K, Young J, Jeffrey L, Kirkland D, Pfuhler S, Carmichael P. 2012a. Reduction of misleading (“false”) positive results in mammalian cell genotoxicity assays. I. Choice of cell type. Mutat Res. 742:11–25.
  • Fowler P, Smith R, Smith K, Young J, Jeffrey L, Carmichael P, Kirkland D, Pfuhler S. 2014. Reduction of misleading (“false”) positive results in mammalian cell genotoxicity assays. III: sensitivity of human cell types to known genotoxic agents. Mutat Res Genet Toxicol Environ Mutagen. 767:28–36.
  • Fowler P, Smith R, Smith K, Young J, Jeffrey L, Kirkland D, Pfuhler S, Carmichael P. 2012b. Reduction of misleading (“false”) positive results in mammalian cell genotoxicity assays. II. Importance of accurate toxicity measurement. Mutat Res. 747:104–117.
  • Frieauff W, Martus HJ, Suter W, Elhajouji A. 2013. Automatic analysis of the micronucleus test in primary human lymphocytes using image analysis. Mutagenesis. 28:15–23.
  • Friedrich A, Olejniczak K. 2011. Evaluation of carcinogenicity studies of medicinal products for human use authorised via the European centralised procedure (1995–2009). Regul Toxicol Pharmacol. 60:225–248.
  • Galloway S, Lorge E, Aardema MJ, Eastmond D, Fellows M, Heflich R, Kirkland D, Levy DD, Lynch AM, Marzin D, et al. 2011. Workshop summary: top concentration for in vitro mammalian cell genotoxicity assays; and report from working group on toxicity measures and top concentration for in vitro cytogenetics assays (chromosome aberrations and micronucleus). Mutat Res. 723:77–83.
  • Galloway SM. 2000. Cytotoxicity and chromosome aberrations in vitro: experience in industry and the case for an upper limit on toxicity in the aberration assay. Environ Mol Mutagen. 35:191–201.
  • Gaylor DW. 2005. Are tumor incidence rates from chronic bioassays telling us what we need to know about carcinogens? Regul Toxicol Pharmacol. 41:128–133.
  • Gold LS, Slone TH, Ames BN. 1998. What do animal cancer tests tell us about human cancer risk?: overview of analyses of the carcinogenic potency database. Drug Metab Rev. 30:359–404.
  • Gollapudi BB, Johnson GE, Hernandez LG, Pottenger LH, Dearfield KL, Jeffrey AM, Julien E, Kim JH, Lovell DP, Macgregor JT, et al. 2013. Quantitative approaches for assessing dose-response relationships in genetic toxicology studies. Environ Mol Mutagen. 54:8–18.
  • Gonzalez L, Sanderson BJ, Kirsch-Volders M. 2011. Adaptations of the in vitro MN assay for the genotoxicity assessment of nanomaterials. Mutagenesis. 26:185–191.
  • Gordon DJ, Resio B, Pellman D. 2012. Causes and consequences of aneuploidy in cancer. Nat Rev Genet. 13:189–203.
  • Gotz C, Hewitt NJ, Jermann E, Tigges J, Kohne Z, Hubenthal U, Krutmann J, Merk HF, Fritsche E. 2012. Effects of the genotoxic compounds, benzo[a]pyrene and cyclophosphamide on phase 1 and 2 activities in EpiDerm™ models. Xenobiotica. 42:526–537.
  • Greenfield RE, Ellwein LB, Cohen SM. 1984. A general probabilistic model of carcinogenesis: analysis of experimental urinary bladder cancer. Carcinogenesis. 5:437–445.
  • Greenwood SK, Hill RB, Sun JT, Armstrong MJ, Johnson TE, Gara JP, Galloway SM. 2004. Population doubling: a simple and more accurate estimation of cell growth suppression in the in vitro assay for chromosomal aberrations that reduces irrelevant positive results. Environ Mol Mutagen. 43:36–44.
  • Gulezian D, Jacobson-Kram D, McCullough CB, Olson H, Recio L, Robinson D, Storer R, Tennant R, Ward JM, Neumann DA. 2000. Use of transgenic animals for carcinogenicity testing: considerations and implications for risk assessment. Toxicol Pathol. 28:482–499.
  • Guyton KZ, Kyle AD, Aubrecht J, Cogliano VJ, Eastmond DA, Jackson M, Keshava N, Sandy MS, Sonawane B, Zhang L, et al. 2009. Improving prediction of chemical carcinogenicity by considering multiple mechanisms and applying toxicogenomic approaches. Mutat Res. 681:230–240.
  • Hanahan D, Weinberg RA. 2000. The hallmarks of cancer. Cell. 100:57–70.
  • Hanahan D, Weinberg RA. 2011. Hallmarks of cancer: the next generation. Cell. 144:646–674.
  • Haseman JK, Clark AM. 1990. Carcinogenicity results for 114 laboratory animal studies used to assess the predictivity of four in vitro genetic toxicity assays for rodent carcinogenicity. Environ Mol Mutagen. 16:15–31.
  • Hastwell PW, Chai LL, Roberts KJ, Webster TW, Harvey JS, Rees RW, Walmsley RM. 2006. High-specificity and high-sensitivity genotoxicity assessment in a human cell line: validation of the GreenScreen HC GADD45a-GFP genotoxicity assay. Mutat Res. 607:160–175.
  • Hastwell PW, Webster TW, Tate M, Billinton N, Lynch AM, Harvey JS, Rees RW, Walmsley RM. 2009. Analysis of 75 marketed pharmaceuticals using the GADD45a-GFP 'GreenScreen HC' genotoxicity assay. Mutagenesis. 24:455–463.
  • HazardExpert Pro. (2015). [cited 2015 April 7]. Available from: http://www.compudrug.com/hazardexpertpro.
  • Hendriks G, Atallah M, Morolli B, Calleja F, Ras-Verloop N, Huijskens I, Raamsman M, van de Water B, Vrieling H. 2012. The ToxTracker assay: novel GFP reporter systems that provide mechanistic insight into the genotoxic properties of chemicals. Toxicol Sci. 125:285–298.
  • Hendriks G, Atallah M, Raamsman M, Morolli B, van der Putten H, Jaadar H, Tijdens I, Esveldt-van Lange R, Mullenders L, van de Water B, et al. 2011. Sensitive DsRed fluorescence-based reporter cell systems for genotoxicity and oxidative stress assessment. Mutat Res. 709–710:49–59.
  • Hendriks G, Derr RS, Misovic B, Morolli B, Calleja FM, Vrieling H. 2015. The extended ToxTracker assay discriminates between induction of DNA damage, oxidative stress and protein misfolding. Toxicol Sci. 150:190–203.
  • Hernandez LG, van Steeg H, Luijten M, van Benthem J. 2009. Mechanisms of non-genotoxic carcinogens and importance of a weight of evidence approach. Mutat Res. 682:94–109.
  • Hewitt NJ, Edwards RJ, Fritsche E, Goebel C, Aeby P, Scheel J, Reisinger K, Ouedraogo G, Duche D, Eilstein J, et al. 2013. Use of human in vitro skin models for accurate and ethical risk assessment: metabolic considerations. Toxicol Sci. 133:209–217.
  • Holsapple MP, Pitot HC, Cohen SM, Boobis AR, Klaunig JE, Pastoor T, Dellarco VL, Dragan YP. 2006. Mode of action in relevance of rodent liver tumors to human cancer risk. Toxicol Sci. 89:51–56.
  • Hu T, Khambatta ZS, Hayden PJ, Bolmarcich J, Binder RL, Robinson MK, Carr GJ, Tiesman JP, Jarrold BB, Osborne R, et al. 2010. Xenobiotic metabolism gene expression in the EpiDermin vitro 3D human epidermis model compared to human skin. Toxicol In Vitro. 24:1450–1463.
  • Huang SM, Abernethy DR, Wang Y, Zhao P, Zineh I. 2013. The utility of modeling and simulation in drug development and regulatory review. J Pharm Sci. 102:2912–2923.
  • Hughes C, Rabinowitz A, Tate M, Birrell L, Allsup J, Billinton N, Walmsley RM. 2012. Development of a high-throughput Gaussia luciferase reporter assay for the activation of the GADD45a gene by mutagens, promutagens, clastogens, and aneugens. J Biomol Screen. 17:1302–1315.
  • ICH. (1995). Guideline S1A: need for carcinogenicity studies of pharmaceuticals. Geneva, Switzerland: ICH.
  • ICH. (1997). Guideline S1B: testing for carcinogenicity of pharmaceuticals. Geneva, Switzerland: ICH.
  • ICH. (2008). Guideline S1C (R2): dose selection for carcinogenicity studies of pharmaceuticals. Geneva, Switzerland: ICH.
  • ICH. (2013). Proposed change to rodent carcinogenicity testing of pharmaceuticals – regulatory notice document. Geneva, Switzerland: ICH.
  • ICH. (2014). Guideline M7: assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. Geneva, Switzerland: ICH.
  • Izumi S, Suyama A, Koyama K. 2003. Radiation-related mortality among offspring of atomic bomb survivors: a half-century of follow-up. Int J Cancer. 107:292–297.
  • Jacobs A. 2005. Prediction of 2-year carcinogenicity study results for pharmaceutical products: how are we doing? Toxicol Sci. 88:18–23.
  • Jacobs AC, Hatfield KP. 2013. History of chronic toxicity and animal carcinogenicity studies for pharmaceuticals. Vet Pathol. 50:324–333.
  • Jacobson-Kram D, Sistare FD, Jacobs AC. 2004. Use of transgenic mice in carcinogenicity hazard assessment. Toxicol Pathol. 32:49–52.
  • Johnson GE, Soeteman-Hernandez LG, Gollapudi BB, Bodger OG, Dearfield KL, Heflich RH, Hixon JG, Lovell DP, MacGregor JT, Pottenger LH, et al. 2014. Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment. Environ Mol Mutagen. 55:609–623.
  • Jones HM, Gardner IB, Watson KJ. 2009. Modelling and PBPK simulation in drug discovery. AAPS J. 11:155–166.
  • Jongeneelen FJ, Berge WF. 2011. A generic, cross-chemical predictive PBTK model with multiple entry routes running as application in MS Excel; design of the model and comparison of predictions with experimental results. Ann Occup Hyg. 55:841–864.
  • Jonker MJ, Bruning O, van Iterson M, Schaap MM, van der Hoeven TV, Vrieling H, Beems RB, de Vries A, van Steeg H, Breit TM, et al. 2009. Finding transcriptomics biomarkers for in vivo identification of (non-)genotoxic carcinogens using wild-type and Xpa/p53 mutant mouse models. Carcinogenesis. 30:1805–1812.
  • Kang SH, Kwon JY, Lee JK, Seo YR. 2013. Recent advances in in vivo genotoxicity testing: prediction of carcinogenic potential using comet and micronucleus assay in animal models. J Cancer Prev. 18:277–288.
  • Karlsson HL, Gliga AR, Calleja FM, Goncalves CS, Wallinder IO, Vrieling H, Fadeel B, Hendriks G. 2014. Mechanism-based genotoxicity screening of metal oxide nanoparticles using the ToxTracker panel of reporter cell lines. Part Fibre Toxicol. 11:41.
  • Karstadt M, Haseman JK. 1997. Effect of discounting certain tumor types/sites on evaluations of carcinogenicity in laboratory animals. Am J Ind Med. 31:485–494.
  • Kimoto T, Chikura S, Suzuki-Okada K, Kobayashi XM, Itano Y, Miura D, Kasahara Y. 2012. Effective use of the Pig-a gene mutation assay for mutagenicity screening: measuring CD59-deficient red blood cells in rats treated with genotoxic chemicals. J Toxicol Sci. 37:943–955.
  • Kinzler KW, Vogelstein B. 1996. Lessons from hereditary colorectal cancer. Cell. 87:159–170.
  • Kirkland D, Aardema M, Henderson L, Muller L. 2005. 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. 584:1–256.
  • Kirkland D, Fowler P. 2010. Further analysis of Ames-negative rodent carcinogens that are only genotoxic in mammalian cells in vitro at concentrations exceeding 1 mM, including retesting of compounds of concern. Mutagenesis. 25:539–553.
  • Kirkland D, Kasper P, Muller L, Corvi R, Speit G. 2008. 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. 653:99–108.
  • Kirkland D, Pfuhler S, Tweats D, Aardema M, Corvi R, Darroudi F, Elhajouji A, Glatt H, Hastwell P, Hayashi M, et al. 2007. 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. 628:31–55.
  • Kirkland D, Zeiger E, Madia F, Corvi R. 2014. Can in vitro mammalian cell genotoxicity test results be used to complement positive results in the Ames test and help predict carcinogenic or in vivo genotoxic activity? II. Construction and analysis of a consolidated database. Mutat Res Genet Toxicol Environ Mutagen. 775–776:69–80.
  • Kirsch-Volders M, Decordier I, Elhajouji A, Plas G, Aardema MJ, Fenech M. 2011. In vitro genotoxicity testing using the micronucleus assay in cell lines, human lymphocytes and 3D human skin models. Mutagenesis. 26:177–184.
  • Klaunig JE, Wang Z, Pu X, Zhou S. 2011. Oxidative stress and oxidative damage in chemical carcinogenesis. Toxicol Appl Pharmacol. 254:86–99.
  • Knudson AG. 2001. Two genetic hits (more or less) to cancer. Nat Rev Cancer. 1:157–162.
  • Knudson AG. Jr. 1971. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 68:820–823.
  • Kodaira M, Izumi S, Takahashi N, Nakamura N. 2004. No evidence of radiation effect on mutation rates at hypervariable minisatellite loci in the germ cells of atomic bomb survivors. Radiat Res. 162:350–356.
  • Lambert IB, Singer TM, Boucher SE, Douglas GR. 2005. Detailed review of transgenic rodent mutation assays. Mutat Res. 590:1–280.
  • LeadScope. 2015. Rodent carcinogenicity Suite. QSAR Models. Columbus, OH: LeadScope Inc.
  • Li HH, Hyduke DR, Chen R, Heard P, Yauk CL, Aubrecht J, Fornace AJ Jr. 2015. Development of a toxicogenomics signature for genotoxicity using a dose-optimization and informatics strategy in human cells. Environ Mol Mutagen. 56:505–519.
  • Lilienblum W, Dekant W, Foth H, Gebel T, Hengstler JG, Kahl R, Kramer PJ, Schweinfurth H, Wollin KM. 2008. Alternative methods to safety studies in experimental animals: role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH). Arch Toxicol. 82:211–236.
  • Loizou G, Hogg A. 2011. MEGen: a physiologically based pharmacokinetic model generator. Front Pharmacol. 2:56.
  • Luecke RH, Pearce BA, Wosilait WD, Doerge DR, Slikker W, Jr, Young JF. 2008. Windows based general PBPK/PD modeling software. Comput Biol Med. 38:962–978.
  • Maunz A, Gutlein M, Rautenberg M, Vorgrimmler D, Gebele D, Helma C. 2013. lazar: a modular predictive toxicology framework. Front Pharmacol. 4:38. doi:10.3389/fphar.2013.00038.
  • Meek ME, Boobis A, Cote I, Dellarco V, Fotakis G, Munn S, Seed J, Vickers C. 2014a. New developments in the evolution and application of the WHO/IPCS framework on mode of action/species concordance analysis. J Appl Toxicol. 34:1–18.
  • Meek ME, Bucher JR, Cohen SM, Dellarco V, Hill RN, Lehman-McKeeman LD, Longfellow DG, Pastoor T, Seed J, Patton DE. 2003. A framework for human relevance analysis of information on carcinogenic modes of action. Crit Rev Toxicol. 33:591–653.
  • Meek ME, Lipscomb JC. 2015. Gaining acceptance for the use of in vitro toxicity assays and QIVIVE in regulatory risk assessment. Toxicology. 332:112–123.
  • Meek ME, Palermo CM, Bachman AN, North CM, Jeffrey Lewis R. 2014b. Mode of action human relevance (species concordance) framework: evolution of the Bradford Hill considerations and comparative analysis of weight of evidence. J Appl Toxicol. 34:595–606.
  • Melis JP, Derks KW, Pronk TE, Wackers P, Schaap MM, Zwart E, van IJcken WF, Jonker MJ, Breit TM, Pothof J, et al. 2014. In vivo murine hepatic microRNA and mRNA expression signatures predicting the (non-)genotoxic carcinogenic potential of chemicals. Arch Toxicol. 88:1023–1034.
  • Melis JP, van Steeg H, Luijten M. 2013. Oxidative DNA damage and nucleotide excision repair. Antioxid Redox Signal. 18:2409–2419.
  • Mena S, Ortega A, Estrela JM. 2009. Oxidative stress in environmental-induced carcinogenesis. Mutat Res. 674:36–44.
  • Miousse IR, Currie R, Datta K, Ellinger-Ziegelbauer H, French JE, Harrill AH, Koturbash I, Lawton M, Mann D, Meehan RR, et al. 2015. Importance of investigating epigenetic alterations for industry and regulators: an appraisal of current efforts by the Health and Environmental Sciences Institute. Toxicology. 335:11–19.
  • Miura D, Dobrovolsky VN, Mittelstaedt RA, Kasahara Y, Katsuura Y, Heflich RH. 2008. Development of an in vivo gene mutation assay using the endogenous Pig-A gene: II. Selection of Pig-A mutant rat spleen T-cells with proaerolysin and sequencing Pig-A cDNA from the mutants. Environ Mol Mutagen. 49:622–630.
  • Moggs JG, Goodman JI, Trosko JE, Roberts RA. 2004. Epigenetics and cancer: implications for drug discovery and safety assessment. Toxicol Appl Pharmacol. 196:422–430.
  • Moolgavkar SH, Knudson AG. Jr. 1981. Mutation and cancer: a model for human carcinogenesis. J Natl Cancer Inst. 66:1037–1052.
  • Morita T, Miyajima A, Hatano A, Honma M. 2014. Effects of lowering the proposed top-concentration limit in an in vitro chromosomal aberration test on assay sensitivity and on the reduction of the number of false positives. Mutat Res Genet Toxicol Environ Mutagen. 769:34–49.
  • Mun GC, Aardema MJ, Hu T, Barnett B, Kaluzhny Y, Klausner M, Karetsky V, Dahl EL, Curren RD. 2009. Further development of the EpiDerm 3D reconstructed human skin micronucleus (RSMN) assay. Mutat Res. 673:92–99.
  • MultiCASE Software. (2015). [cited 2015 April 7]. Available from: http://multicase.com/.
  • Nestorov I. 2007. Whole-body physiologically based pharmacokinetic models. Expert Opin Drug Metab Toxicol. 3:235–249.
  • NRC (National Research Council). (2007). Toxicity testing in the 21st century: a vision and a strategy. Ontario, Canada: National Research Council.
  • NTP (National Toxicology Program), U.S. Department of Health and Human Services, Public Health Service. (2014). Report on carcinogens. 13th ed. Research Triangle Park, NC: NTP.
  • OECD. (1997a). Test No. 471: bacterial reverse mutation test. Paris, France: OECD.
  • OECD. (1997b). Test No. 476: in vitro mammalian cell gene mutation test. Paris, France: OECD.
  • OECD. (2007). Detailed review paper on cell transformation assays for detection of chemical carcinogens. Series on testing and assessment. Paris, France: OECD Environment, Health and Safety Publications.
  • OECD. (2013a). Guidance document on developing and asssessing adverse outcome pathways. Series on testing and assessment No. 184. Paris, France: OECD Environment, Health and Safety Publications.
  • OECD. (2013b). Test No. 488: transgenic rodent somatic and germ cell gene mutation assays. Paris, France: OECD Publishing.
  • OECD. (2014a). Draft guidance document: in vitro syrian hamster embryo (SHE) cell transformation assay (December 2014). Paris, France: OECD.
  • OECD. (2014b). Draft guidance document: in vitro syrian hamster embryo (SHE) cell transformation assay (July 2014). Paris, France: OECD.
  • OECD. (2014c). Guidance on grouping of chemicals. 2nd ed. Series on Testing and No. 194. Paris, France: OECD Environment, Health and Safety Publications.
  • OECD. (2014d). Test No. 473: in vitro mammalian chromosomal aberration test. Paris, France: OECD Publishing.
  • OECD. (2014e). Test No. 474: mammalian erythrocyte micronucleus test. Paris, France: OECD Publishing.
  • OECD. (2014f). Test No. 475: mammalian bone marrow chromosomal aberration test. Paris, France: OECD Publishing.
  • OECD. (2014g). Test No. 487: in vitro mammalian cell micronucleus test. Paris, France: OECD Publishing.
  • OECD. (2014h). Test No. 489: in vivo mammalian alkaline comet assay. Paris, France: OECD Publishing.
  • OECD. (2015a). Draft guidance document on Bhas 42 cell transformation assay. Paris, France: OECD.
  • OECD. (2015b). QSAR Toolbox; software for grouping chemicals into categories and filling datagaps in (eco)toxicity data needed for assessing the hazard of chemicals. Paris, France: OECD.
  • Olaharski AJ, Albertini S, Mueller L, Zeller A, Struwe M, Gocke E, Kolaja K. 2011. GADD45α induction in the GreenScreen HC indicator assay does not occur independently of cytotoxicity. Environ Mol Mutagen. 52:28–34.
  • Osimitz TG, Droege W, Boobis AR, Lake BG. 2013. Evaluation of the utility of the lifetime mouse bioassay in the identification of cancer hazards for humans. Food Chem Toxicol. 60:550–562.
  • Parry JM, Jenkins GJ, Haddad F, Bourner R, Parry EM. 2000. In vitro and in vivo extrapolations of genotoxin exposures: consideration of factors which influence dose-response thresholds. Mutat Res. 464:53–63.
  • Parry JM, Parry E, Phrakonkham P, Corvi R. 2010. Analysis of published data for top concentration considerations in mammalian cell genotoxicity testing. Mutagenesis. 25:531–538.
  • Passerini V, Ozeri-Galai E, de Pagter MS, Donnelly N, Schmalbrock S, Kloosterman WP, Kerem B, Storchova Z. 2016. The presence of extra chromosomes leads to genomic instability. Nat Commun. 7:10754.
  • Pastoor T, Stevens J. 2005. Historical perspective of the cancer bioassay. Scand J Work Environ Health. 31:129–140. discussion 119–122.
  • Patlewicz G, Jeliazkova N, Safford RJ, Worth AP, Aleksiev B. 2008. An evaluation of the implementation of the Cramer classification scheme in the Toxtree software. SAR QSAR Environ Res. 19:495–524.
  • Pfuhler S, Fautz R, Ouedraogo G, Latil A, Kenny J, Moore C, Diembeck W, Hewitt NJ, Reisinger K, Barroso J. 2014. The Cosmetics Europe strategy for animal-free genotoxicity testing: project status up-date. Toxicol In Vitro. 28:18–23.
  • Pfuhler S, Kirkland D, Kasper P, Hayashi M, Vanparys P, Carmichael P, Dertinger S, Eastmond D, Elhajouji A, Krul C, et al. 2009. Reduction of use of animals in regulatory genotoxicity testing: identification and implementation opportunities-Report from an ECVAM workshop. Mutat Res. 680:31–42.
  • Pogribny IP, Beland FA. 2012. DNA methylome alterations in chemical carcinogenesis. Cancer Lett. 334:39–45.
  • Pogribny IP, Rusyn I. 2013. Environmental toxicants, epigenetics, and cancer. Adv Exp Med Biol. 754:215–232.
  • Pottenger LH, Gollapudi BB. 2010. Genotoxicity testing: moving beyond qualitative “screen and bin" approach towards characterization of dose-response and thresholds”. Environ Mol Mutagen. 51:792–799.
  • Pratt IS, Barron T. 2003. Regulatory recognition of indirect genotoxicity mechanisms in the European Union. Toxicol Lett. 140–141:53–62.
  • Reddy MV, Sistare FD, Christensen JS, Deluca JG, Wollenberg GK, Degeorge JJ. 2010. An evaluation of chronic 6- and 12-month rat toxicology studies as predictors of 2-year tumor outcome. Vet Pathol. 47:614–629.
  • Reifferscheid G, Maes HM, Allner B, Badurova J, Belkin S, Bluhm K, Brauer F, Bressling J, Domeneghetti S, Elad T, et al. 2012. International round-robin study on the Ames fluctuation test. Environ Mol Mutagen. 53:185–197.
  • Reus AA, Reisinger K, Downs TR, Carr GJ, Zeller A, Corvi R, Krul CA, Pfuhler S. 2013. Comet assay in reconstructed 3D human epidermal skin models-investigation of intra- and inter-laboratory reproducibility with coded chemicals. Mutagenesis. 28:709–720.
  • 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.
  • Romer M, Eichner J, Metzger U, Templin MF, Plummer S, Ellinger-Ziegelbauer H, Zell A. 2014. Cross-platform toxicogenomics for the prediction of non-genotoxic hepatocarcinogenesis in rat. PLoS One. 9:e97640.
  • Rossnerova A, Spatova M, Schunck C, Sram RJ. 2011. Automated scoring of lymphocyte micronuclei by the MetaSystems Metafer image cytometry system and its application in studies of human mutagen sensitivity and biodosimetry of genotoxin exposure. Mutagenesis. 26:169–175.
  • Rostami-Hodjegan A. 2012. Physiologically based pharmacokinetics joined with in vitro-in vivo extrapolation of ADME: a marriage under the arch of systems pharmacology. Clin Pharmacol Ther. 92:50–61.
  • Rotroff DM, Wetmore BA, Dix DJ, Ferguson SS, Clewell HJ, Houck KA, Lecluyse EL, Andersen ME, Judson RS, Smith CM, et al. 2010. Incorporating human dosimetry and exposure into high-throughput in vitro toxicity screening. Toxicol Sci. 117:348–58.
  • SCCS. (2015). Notes of Guidance (NoG) for the Testing of Cosmetic Ingredients and their Safety Evaluation, 9th Revision. SCCS/1564/15, 29 September 2015.
  • Schaap MM, Wackers PF, Zwart EP, Huijskens I, Jonker MJ, Hendriks G, Breit TM, van Steeg H, van de Water B, Luijten M. 2014. A novel toxicogenomics-based approach to categorize (non-)genotoxic carcinogens. Arch Toxicol. 89:2413–2427.
  • Schaap MM, Zwart EP, Wackers PF, Huijskens I, van de Water B, Breit TM, van Steeg H, Jonker MJ, Luijten M. 2012. Dissecting modes of action of non-genotoxic carcinogens in primary mouse hepatocytes. Arch Toxicol. 86:1717–1727.
  • Schetter AJ, Heegaard NH, Harris CC. 2010. Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis. 31:37–49.
  • Seed J, Carney EW, Corley RA, Crofton KM, DeSesso JM, Foster PM, Kavlock R, Kimmel G, Klaunig J, Meek ME, et al. 2005. Overview: using mode of action and life stage information to evaluate the human relevance of animal toxicity data. Crit Rev Toxicol. 35:664–672.
  • Silva Lima B, Van der Laan JW. 2000. Mechanisms of nongenotoxic carcinogenesis and assessment of the human hazard. Regul Toxicol Pharmacol. 32:135–143.
  • Simpson K, Bevan N, Hastwell P, Eidam P, Shah P, Gogo E, Rees S, Brown A. 2013. The BlueScreen-384 assay as an indicator of genotoxic hazard potential in early-stage drug discovery. J Biomol Screen. 18:441–452.
  • Sistare FD, Morton D, Alden C, Christensen J, Keller D, Jonghe SD, Storer RD, Reddy MV, Kraynak A, Trela B, et al. 2011. An analysis of pharmaceutical experience with decades of rat carcinogenicity testing: support for a proposal to modify current regulatory guidelines. Toxicol Pathol. 39:716–744.
  • Sonich-Mullin C, Fielder R, Wiltse J, Baetcke K, Dempsey J, Fenner-Crisp P, Grant D, Hartley M, Knaap A, Kroese D, et al. 2001. IPCS conceptual framework for evaluating a mode of action for chemical carcinogenesis. Regul Toxicol Pharmacol. 34:146–152.
  • Spalding JW, French JE, Stasiewicz S, Furedi-Machacek M, Conner F, Tice RR, Tennant RW. 2000. Responses of transgenic mouse lines p53(+/−) and Tg.AC to agents tested in conventional carcinogenicity bioassays. Toxicol Sci. 53:213–223.
  • Speit G, Kojima H, Burlinson B, Collins AR, Kasper P, Plappert-Helbig U, Uno Y, Vasquez M, Beevers C, De Boeck M, et al. 2015. Critical issues with the in vivo comet assay: a report of the comet assay working group in the 6th International Workshop on Genotoxicity Testing (IWGT). Mutat Res Genet Toxicol Environ Mutagen. 783:6–12.
  • Storer RD, French JE, Haseman J, Hajian G, LeGrand EK, Long GG, Mixson LA, Ochoa R, Sagartz JE, Soper KA. 2001. P53+/- hemizygous knockout mouse: overview of available data. Toxicol Pathol. 29:30–50.
  • Suter GW, II, Cormier SM. 2011. Why and how to combine evidence in environmental assessments: weighing evidence and building cases. Sci Total Environ. 409:1406–1417.
  • Tennant RW. 1993. Stratification of rodent carcinogenicity bioassay results to reflect relative human hazard. Mutat Res. 286:111–118.
  • Tennant RW, Margolin BH, Shelby MD, Zeiger E, Haseman JK, Spalding J, Caspary W, Resnick M, Stasiewicz S, Anderson B, et al. 1987. Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays. Science. 236:933–941.
  • Tennant RW, Spalding J. 1996. Predictions for the outcome of rodent carcinogenicity bioassays: identification of trans-species carcinogens and noncarcinogens. Environ Health Perspect. 104:1095–1100.
  • Tennant RW, Spalding J, French JE. 1996. Evaluation of transgenic mouse bioassays for identifying carcinogens and noncarcinogens. Mutat Res. 365:119–127.
  • Thomson JP, Moggs JG, Wolf CR, Meehan RR. 2014. Epigenetic profiles as defined signatures of xenobiotic exposure. Mutat Res Genet Toxicol Environ Mutagen. 764–765:3–9.
  • Tice RR, Agurell E, Anderson D, Burlinson B, Hartmann A, Kobayashi H, Miyamae Y, Rojas E, Ryu JC, Sasaki YF. 2000. Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environ Mol Mutagen. 35:206–221.
  • Tollefsen KE, Scholz S, Cronin MT, Edwards SW, de Knecht J, Crofton K, Garcia-Reyero N, Hartung T, Worth A, Patlewicz G. 2014. Applying adverse outcome pathways (AOPs) to support integrated approaches to testing and assessment (IATA). Regul Toxicol Pharmacol. 70:629–640.
  • Uehara T, Minowa Y, Morikawa Y, Kondo C, Maruyama T, Kato I, Nakatsu N, Igarashi Y, Ono A, Hayashi H, et al. 2011. Prediction model of potential hepatocarcinogenicity of rat hepatocarcinogens using a large-scale toxicogenomics database. Toxicol Appl Pharmacol. 255:297–306.
  • Uno Y, Morita T, Luijten M, Beevers C, Hamada S, Itoh S, Ohyama W, Takasawa H. 2015a. Micronucleus test in rodent tissues other than liver or erythrocytes: Report of the IWGT working group. Mutat Res Genet Toxicol Environ Mutagen. 783:19–22.
  • Uno Y, Morita T, Luijten M, Beevers C, Hamada S, Itoh S, Ohyama W, Takasawa H. 2015b. Recommended protocols for the liver micronucleus test: Report of the IWGT working group. Mutat Res Genet Toxicol Environ Mutagen. 783:13–18.
  • U.S. Environmental Protection Agency. (2005). Guidelines for carcinogen risk assessment. Risk Assessment Forum, Washington, DC. EPA/639/P-03/001F.
  • US FDA (Food and Drug Administration), U.S. Department of Health and Human Services, Center for Drug Evaluation and Research (CDER). (2012). Guidance for Industry. Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations.
  • Usui T, Mutai M, Hisada S, Takoaka M, Soper KA, McCullough B, Alden C. 2001. CB6F1-rasH2 mouse: overview of available data. Toxicol Pathol. 29:90–108.
  • van Delft JH, van Agen E, van Breda SG, Herwijnen MH, Staal YC, Kleinjans JC. 2005. Comparison of supervised clustering methods to discriminate genotoxic from non-genotoxic carcinogens by gene expression profiling. Mutat Res. 575:17–33.
  • Van der Laan JW, DeGeorge JJ, Sistare FD, Moggs JG. 2013. Toward more scientific relevance in carcinogenicity testing. In: Van der Laan JW, DeGeorge JJ, editors. Global approach in safety testing. New York: Springer-Verlag.
  • Van der Laan JW, Kasper P, Silva Lima B, Jones DJ, Pasanen M. 2016. Critical analysis of carcinogenicity study outcomes – relation with pharmacological properties. Crit Rev Toxicol. [in press].
  • van Eijkeren JC, Bakker MI, Zeilmaker MJ. 2006. A simple steady-state model for carry-over of aflatoxins from feed to cow's milk. Food Addit Contam. 23:833–838.
  • van Kreijl CF, McAnulty PA, Beems RB, Vynckier A, van Steeg H, Fransson-Steen R, Alden CL, Forster R, van der Laan JW, Vandenberghe J. 2001. Xpa and Xpa/p53+/- knockout mice: overview of available data. Toxicol Pathol. 29:117–127.
  • Van Oosterhout JP, Van der Laan JW, De Waal EJ, Olejniczak K, Hilgenfeld M, Schmidt V, Bass R. 1997. The utility of two rodent species in carcinogenic risk assessment of pharmaceuticals in Europe. Regul Toxicol Pharmacol. 25:6–17.
  • Vasquez MZ. 2012. Recommendations for safety testing with the in vivo comet assay. Mutat Res. 747:142–156.
  • Vasseur P, Lasne C. 2012. OECD Detailed Review Paper (DRP) number 31 on “Cell Transformation Assays for Detection of Chemical Carcinogens”: main results and conclusions. Mutat Res. 744:8–11.
  • Vogelstein B, Kinzler KW. 1993. The multistep nature of cancer. Trends Genet. 9:138–141.
  • Walmsley RM, Tate M. 2012. The GADD45a-GFP GreenScreen HC assay. Methods Mol Biol. 817:231–250.
  • Watanabe T, Suzuki T, Natsume M, Nakajima M, Narumi K, Hamada S, Sakuma T, Koeda A, Oshida K, Miyamoto Y, et al. 2012. Discrimination of genotoxic and non-genotoxic hepatocarcinogens by statistical analysis based on gene expression profiling in the mouse liver as determined by quantitative real-time PCR. Mutat Res. 747:164–175.
  • Waters MD, Jackson M, Lea I. 2010. Characterizing and predicting carcinogenicity and mode of action using conventional and toxicogenomics methods. Mutat Res. 705:184–200.
  • Wetmore BA. 2015. Quantitative in vitro-to-in vivo extrapolation in a high-throughput environment. Toxicology. 332:94–101.
  • Wetmore BA, Wambaugh JF, Ferguson SS, Li L, Clewell HJ 3rd, Judson RS, Freeman K, Bao W, Sochaski MA, Chu TM, et al. 2013. Relative impact of incorporating pharmacokinetics on predicting in vivo hazard and mode of action from high-throughput in vitro toxicity assays. Toxicol Sci. 132:327–346.
  • Whitwell J, Smith R, Jenner K, Lyon H, Wood D, Clements J, Aschcroft-Hawley K, Gollapudi B, Kirkland D, Lorge E, et al. 2015. Relationships between p53 status, apoptosis and induction of micronuclei in different human and mouse cell lines in vitro: implications for improving existing assays. Mutat Res Genet Toxicol Environ Mutagen. 789–790:7–27.
  • WHO (World Health Organization). (2010). Characterization and application of physiologically based pharmacokinetic models in risk assessment, International Programme on Chemical Safety. Geneva, Switzerland: WHO.
  • Wilk-Zasadna I, Bernasconi C, Pelkonen O, Coecke S. 2015. Biotransformation in vitro: an essential consideration in the quantitative in vitro-to-in vivo extrapolation (QIVIVE) of toxicity data. Toxicology. 332:8–19.
  • Woo YT, Lai DY. 2003. Mechanism of action of chemical carcinogens and their role in structure-activity relationships analysis and risk assessment. In: Benigni R, editor. Quantitative structure-activity relationship (QSAR) analysis of mutagens and carcinogens. Boca Raton (FL): CRC Press.
  • Wu S, Blackburn K, Amburgey J, Jaworska J, Federle T. 2010. A framework for using structural, reactivity, metabolic and physicochemical similarity to evaluate the suitability of analogs for SAR-based toxicological assessments. Regul Toxicol Pharmacol. 56:67–81.
  • Yamada F, Sumida K, Uehara T, Morikawa Y, Yamada H, Urushidani T, Ohno Y. 2013. Toxicogenomics discrimination of potential hepatocarcinogenicity of non-genotoxic compounds in rat liver. J Appl Toxicol. 33:1284–1293.
  • Yamamoto S, Urano K, Koizumi H, Wakana S, Hioki K, Mitsumori K, Kurokawa Y, Hayashi Y, Nomura T. 1998. Validation of transgenic mice carrying the human prototype c-Ha-ras gene as a bioassay model for rapid carcinogenicity testing. Environ Health Perspect. 106:57–69.
  • Yauk CL, Aardema MJ, van Benthem J, Bishop JB, Dearfield KL, DeMarini DM, Dubrova YE, Honma M, Lupski JR, Marchetti F, et al. 2015. Approaches for identifying germ cell mutagens: report of the 2013 IWGT workshop on germ cell assays(⋆). Mutat Res Genet Toxicol Environ Mutagen. 783:36–54.
  • Yoon M, Campbell JL, Andersen ME, Clewell HJ. 2012. Quantitative in vitro to in vivo extrapolation of cell-based toxicity assay results. Crit Rev Toxicol. 42:633–652.
  • Zeiger E. 1998. Identification of rodent carcinogens and noncarcinogens using genetic toxicity tests: premises, promises, and performance. Regul Toxicol Pharmacol. 28:85–95.
  • Zeiger E, Haseman JK, Shelby MD, Margolin BH, Tennant RW. 1990. Evaluation of four in vitro genetic toxicity tests for predicting rodent carcinogenicity: confirmation of earlier results with 41 additional chemicals. Environ Mol Mutagen. 16:1–14.
  • Zhao P, Zhang L, Grillo JA, Liu Q, Bullock JM, Moon YJ, Song P, Brar SS, Madabushi R, Wu TC, et al. 2011. Applications of physiologically based pharmacokinetic (PBPK) modeling and simulation during regulatory review. Clin Pharmacol Ther. 89:259–267.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.