Archives of Toxicology

, Volume 85, Issue 5, pp 367–485 | Cite as

Alternative (non-animal) methods for cosmetics testing: current status and future prospects—2010

  • Sarah Adler
  • David Basketter
  • Stuart Creton
  • Olavi Pelkonen
  • Jan van Benthem
  • Valérie ZuangEmail author
  • Klaus Ejner Andersen
  • Alexandre Angers-Loustau
  • Aynur Aptula
  • Anna Bal-Price
  • Emilio Benfenati
  • Ulrike Bernauer
  • Jos Bessems
  • Frederic Y. Bois
  • Alan Boobis
  • Esther Brandon
  • Susanne Bremer
  • Thomas Broschard
  • Silvia Casati
  • Sandra Coecke
  • Raffaella Corvi
  • Mark Cronin
  • George Daston
  • Wolfgang Dekant
  • Susan Felter
  • Elise Grignard
  • Ursula Gundert-Remy
  • Tuula Heinonen
  • Ian Kimber
  • Jos Kleinjans
  • Hannu Komulainen
  • Reinhard Kreiling
  • Joachim Kreysa
  • Sofia Batista Leite
  • George Loizou
  • Gavin Maxwell
  • Paolo Mazzatorta
  • Sharon Munn
  • Stefan Pfuhler
  • Pascal Phrakonkham
  • Aldert Piersma
  • Albrecht Poth
  • Pilar Prieto
  • Guillermo Repetto
  • Vera Rogiers
  • Greet Schoeters
  • Michael Schwarz
  • Rositsa Serafimova
  • Hanna Tähti
  • Emanuela Testai
  • Joost van Delft
  • Henk van Loveren
  • Mathieu Vinken
  • Andrew Worth
  • José-Manuel Zaldivar
Review Article


The 7th amendment to the EU Cosmetics Directive prohibits to put animal-tested cosmetics on the market in Europe after 2013. In that context, the European Commission invited stakeholder bodies (industry, non-governmental organisations, EU Member States, and the Commission’s Scientific Committee on Consumer Safety) to identify scientific experts in five toxicological areas, i.e. toxicokinetics, repeated dose toxicity, carcinogenicity, skin sensitisation, and reproductive toxicity for which the Directive foresees that the 2013 deadline could be further extended in case alternative and validated methods would not be available in time. The selected experts were asked to analyse the status and prospects of alternative methods and to provide a scientifically sound estimate of the time necessary to achieve full replacement of animal testing. In summary, the experts confirmed that it will take at least another 7–9 years for the replacement of the current in vivo animal tests used for the safety assessment of cosmetic ingredients for skin sensitisation. However, the experts were also of the opinion that alternative methods may be able to give hazard information, i.e. to differentiate between sensitisers and non-sensitisers, ahead of 2017. This would, however, not provide the complete picture of what is a safe exposure because the relative potency of a sensitiser would not be known. For toxicokinetics, the timeframe was 5–7 years to develop the models still lacking to predict lung absorption and renal/biliary excretion, and even longer to integrate the methods to fully replace the animal toxicokinetic models. For the systemic toxicological endpoints of repeated dose toxicity, carcinogenicity and reproductive toxicity, the time horizon for full replacement could not be estimated.


Alternative methods Toxicokinetics Skin sensitisation Repeated dose toxicity Carcinogenicity Reproductive toxicity 

Supplementary material

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  1. Aardema MJ, Barnett B, Khambatta ZS, Reisinger K, Ouedrago-Arras G, Faquet B, Ginestet A, Mun GC, Dahl EL, Hewitt NJ, Corvi R, Curren RC (2010) International pre-validation studies of the EpiDerm™ 3D human reconstructed skin micronucleus (RSMN) assay: transferability and reproducibility. Mutat Res 701:123–131PubMedGoogle Scholar
  2. Adler S, Lindqvist J, Uddenberg K, Hyllner J, Strehl R (2008a) Testing potential developmental toxicants with a cytotoxicity assay based on human embryonic stem cells. Altern Lab Anim 36:129–140PubMedGoogle Scholar
  3. Adler S, Pellizzer C, Hareng L, Hartung T, Bremer S (2008b) First steps in establishing a developmental toxicity test method based on human embryonic stem cells. Toxicol In Vitro 22:200–211PubMedGoogle Scholar
  4. Adler S, Bicker G, Bigalke H, Bishop C, Blümel J, Dressler D, Fitzgerald J, Gessler F, Heuschen H, Kegel B, Luch A, Milne C, Pickett A, Ratsch H, Ruhdel I, Sesardic D, Stephens M, Stiens G, Thornton PD, Thürmer R, Vey M, Spielmann H, Grune B, Liebsch M (2010) The current scientific and legal status of alternative methods to the LD50 test for botulinum neurotoxin potency testing. The report and recommendations of a ZEBET expert meeting. Altern Lab Anim 38(4):315–330Google Scholar
  5. Aeby P, Python F, Goebel C (2007) Skin sensitisation: understanding the in vivo situation for the development of reliable in vitro test approaches. ALTEX 24(spec no):3–5Google Scholar
  6. Agdeppa ED, Spilker ME (2009) A review of imaging agent development. AAPS J 11(2):286–299PubMedGoogle Scholar
  7. Aleksic M, Thain E, Roger D, Saib O, Davies M, Li J, Aptula A, Zazzeroni R (2009) Reactivity profiling: covalent modification of single nucleophile peptides for skin sensitisation risk assessment. Toxicol Sci 108(2):401–411PubMedGoogle Scholar
  8. Aliahmadi E, Gramlich R, Grützkau A, Hitzler M, Krüger M, Baumgrass R, Schreiner M, Wittig B, Wanner R, Peiser M (2009) TLR2-activated human langerhans cells promote Th17 polarization via IL-1beta, TGF-beta and IL-23. Eur J Immunol 39(5):1221–1230PubMedGoogle Scholar
  9. Allen DD, Geldenhuys WJ (2006) Molecular Modelling of blood-barrier nutrient transporters: in silico basis for evaluation of potential drug delivery to the central nervous system. Life Sci 78:1029–1033PubMedGoogle Scholar
  10. Allen JW, Khetani SR, Bhatia SN (2005) In vitro zonation and toxicity in a hepatocyte bioreactor. Toxicol Sci 84(1):110–119PubMedGoogle Scholar
  11. Allen BC, Hack CE, Clewell HJ (2007) Use of Markov Chain Monte Carlo analysis with a physiologically-based pharmacokinetic model of methylmercury to estimate exposures in US women of childbearing age. Risk Anal 27:947–959PubMedGoogle Scholar
  12. Ames BN, Gold LS (1991) Response. Science 251:607–608PubMedGoogle Scholar
  13. Andersen ME (1995) What do we mean by dose? Inhalation Toxicol 7:909–915Google Scholar
  14. Andersen KE, Maibach HI (1985) Guinea pig sensitisation assays. An overview. In: Andersen KE, Maibach HI (eds) Contact allergy. Predictive tests in guinea pigs. Karger, Basel, pp 263–290Google Scholar
  15. Andersen KE, Vølund AA, Frankild S (1995) The guinea pig maximization test—with a multiple dose design. Acta Derm Venereol 75(6):463–469PubMedGoogle Scholar
  16. Aninat C, Piton A, Glaise D, Le Charpentier T, Langouët S, Morel F, Guguen-Guillouzo C, Guillouzo A (2006) Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma RG cells. Drug Metab Dispos 34(1):75–83PubMedGoogle Scholar
  17. Anon (1967) Report of the WHO scientific group. WHO principles for the testing of drugs for teratogenicity. WHO technical reports series 18, p 364Google Scholar
  18. Anon (1998) American society for testing and materials (ASTM). Standard guide for conducting the frog embryo teratogenesis assay—xenopus (FETAX), E1439-91 annual book of ASTM standards. ASTM, Philadelphia, 11.05, pp 826–836Google Scholar
  19. Anon (2003) Globally harmonised system of classification and labelling of chemicals (GHS). Part 3: health and environmental hazards. United Nations Organisation, New York, pp 151–158Google Scholar
  20. Anon (2010a) The official ReProTect Website. Accessed on 12 July 2010
  21. Anon (2010b) Embryotoxicity testing in post-implantation embryo culture—method of piersma INVITTOX no 123. Accessed on 13 July 2010
  22. Ao L, Liu JY, Liu WB, Gao LH, Hu R, Fang ZJ, Zhen ZX, Huang MH, Yang MS, Cao J (2010) Comparison of gene expression profiles in BALB/c 3T3 transformed foci exposed to tumor promoting agents. Toxicol In Vitro 24:430–438PubMedGoogle Scholar
  23. Api AM, Basketter DA, Cadby PA, Cano MF, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford B (2008) Dermal sensitisation quantitative risk assessment (QRA) for fragrance ingredients. Regul Toxicol Pharmacol 52(1):3–23PubMedGoogle Scholar
  24. Aptula AO, Roberts DW (2006) Mechanistic applicability domains for non animal-based prediction of toxicological end points: general principles and application to reactive toxicity. Chem Res Toxicol 19(8):1097–1105PubMedGoogle Scholar
  25. Aptula AO, Roberts DW, Pease C (2007) Haptens, prohaptens and prehaptens, or electrophiles and proelectrophiles. Contact Derm 56(1):54–56PubMedGoogle Scholar
  26. Artola-Garicano E, Vaes WH, Hermens JL (2000) Validation of negligible depletion solid-phase microextraction as a tool to determine tissue/blood partition coefficients for semivolatile and nonvolatile organic chemicals. Toxicol Appl Pharmacol 166:138–144PubMedGoogle Scholar
  27. Aschauer L, Wilmes A, Leonard MO, Pfaller W, Jennings P (2010) In vitro perfusion system for semi-automation of long-term repeat dose toxicity testing. ALTEX 27(suppl 2/10):12–13Google Scholar
  28. Ashby J (2001) Expectations for transgenic rodent cancer bioassay models. Toxicol Pathol 29(suppl):177–182PubMedGoogle Scholar
  29. Ashikaga T, Yoshida Y, Hirota M, Yoneyama K, Itagaki H, Sakaguchi H, Miyazawa M, Ito Y, Suzuki H, Toyoda H (2006) Development of an in vitro skin sensitisation test using human cell lines: the human cell line activation test (h-CLAT). I. Optimization of the h-CLAT protocol. Toxicol In Vitro 20(5):767–773Google Scholar
  30. Attardi BJ, Hild SA, Reel JR (2006) Dimethandrolone undecanoate: a new potent orally active androgen with progestational activity. Endocrinology 147:3016–3026PubMedGoogle Scholar
  31. Augustine KA (2009) HESI DART. Alternative assays workshop II: generation and preliminary assessment of a zebrafish teratogenicity assay. Accessed on 11 July 2010
  32. Augustine-Rauch K, Zhang CX, Panzica-Kelly JM (2010) In vitro developmental toxicology assays: a review of the state of the science of rodent and zebrafish whole embryo culture and embryonic stem cell assays. Birth Defects Res C Embryo Today 90:87–98PubMedGoogle Scholar
  33. Bailey JKABJ (2005) The future of teratology is in vitro. Biogenic Amines 19:97–145Google Scholar
  34. Baillie TA (2006) Future of toxicology-metabolic activation and drug design: challenges and opportunities in chemical toxicology. Chem Res Toxicol 19:889–893PubMedGoogle Scholar
  35. Baillie TA (2008) Metabolism and toxicity of drugs. Two decades of progress in industrial drug metabolism. Chem Res Toxicol 21:129–137PubMedGoogle Scholar
  36. Balls M, Hellsten E (2002) Statement of the scientific validity of the embryonic stem cell test (EST)—an in Vitro test for embryotoxicity. Altern Lab Anim 30:265–268PubMedGoogle Scholar
  37. Bal-Price A, Suñol C, Dieter G, Weiss G, van Vliet E, Westerink RHS, Costa LG (2008) Application of in vitro neurotoxicity testing for regulatory purposes: symposium III summary and research needs. Neurotoxicology 29(3):520–531PubMedGoogle Scholar
  38. Banas A, Teratani T, Yamamoto Y, Tokuhara M, Takeshita F, Quinn G, Okochi H, Ochiya T (2007) Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes. Hepatology 46(1):219–228PubMedGoogle Scholar
  39. Bantle JA, Finch RA, Fort DJ, Stover EL, Hull M, Kumsher-King M, Gaudet-Hull AM (1999) Phase III interlaboratory study of FETAX. Part 3. FETAX validation using 12 compounds with and without an exogenous metabolic activation system. J Appl Toxicol 19:447–472PubMedGoogle Scholar
  40. Barlow S (2005) Threshold of toxicological concern (TTC). A tool for assessing substances of unknown toxicity present at low levels in the diet. ILSI Europe concise monograph series, The International Life Sciences Institute (ILSI), EuropeGoogle Scholar
  41. Barratt MD, Castell JV, Chamberlain M, Combes RD, Dearden JC, Fentem JH, Gerner I, Giuliani A, Gray TJB, Livingstone DJ, Provan WML, Rutten F, Verhaar HJM, Zbinden P (1995) The integrated use of alternative approaches for predicting toxic hazard—the report and recommendations of ECVAM workshop-8. ATLA 23:410–429Google Scholar
  42. Barton HA (2009) Biological modeling as a method for data evaluation and integration in toxicology. Hum Exp Toxicol 28(2–3):143–145PubMedGoogle Scholar
  43. Barton HA, Pastoor TP, Baetcke K, Chambers JE, Diliberto J, Doerrer NG, Driver JH, Hastings CE, Iyengar S, Krieger R, Stahl B, Timchalk C (2006) The acquisition and application of absorption, distribution, metabolism, and excretion (ADME) data in agricultural chemical safety assessments. Crit Rev Toxicol 36(1):9–35PubMedGoogle Scholar
  44. Barton HA, Chiu WA, Setzer RW, Andersen ME, Bailer AJ, Bois FY, Dewoskin RS, Hays S, Johanson G, Jones N, Loizou G, Macphail RC, Portier CJ, Spendiff M, Tan YM (2007) Characterizing uncertainty and variability in physiologically based pharmacokinetic models: state of the science and needs for research and implementation. ToxicologicalGoogle Scholar
  45. Basketter DA (2009) The human repeated insult patch test in the 21st century: a commentary on ethics and validity. Cutan Ocul Toxicol 28(2):49–53PubMedGoogle Scholar
  46. Basketter DA (2010) Methyldibromoglutaronitrile, skin sensitisation and quantitative risk assessment. Cutan Ocul Toxicol 29(1):4–9PubMedGoogle Scholar
  47. Basketter DA, Kimber I (2010a) Contact hypersensitivity. In: McQueen CA (ed) Comprehensive toxicology, vol 5, 2nd edn edn. Elsevier, Kidlington, pp 397–411Google Scholar
  48. Basketter DA, Kimber I (2010b) Skin sensitization, false positives and false negatives: experience with guinea pig assays. J Appl Toxicol 30(5):381–386PubMedGoogle Scholar
  49. Basketter DA, Lea LJ, Dickens A, Briggs D, Pate I, Dearman RJ, Kimber I (1999) A comparison of statistical approaches to the derivation of EC3 values from local lymph node assay dose responses. J Appl Toxicol 19(4):261–266PubMedGoogle Scholar
  50. Basketter DA, Andersen KE, Lidén C, van Loveren H, Boman A, Kimber I, Alanko K, Berggren E (2005a) Evaluation of the skin sensitising potency of chemicals using existing methods and considerations of relevance for elicitation. Contact Derm 52(1):39–43PubMedGoogle Scholar
  51. Basketter DA, Casati S, Gerberick GF, Griem P, Philips B, Worth A (2005b) Skin Sensitisation. Altern Lab Anim 33(suppl 1):83–103PubMedGoogle Scholar
  52. Basketter DA, Clapp C, Jefferies D, Safford B, Ryan CA, Gerberick GF, Dearman RJ, Kimber I (2005c) Predictive identification of human skin sensitisation thresholds. Contact Derm 53(5):260–267PubMedGoogle Scholar
  53. Basketter DA, Gerberick GF, Kimber I (2007a) The local lymph node assay EC3 value: status of validation. Contact Derm 57(2):70–75PubMedGoogle Scholar
  54. Basketter DA, Kan-King-Yu D, Dierkes P, Jowsey IR (2007b) Does irritation potency contribute to the skin sensitisation potency of contact allergens? Cutan Ocul Toxicol 26(4):279–286PubMedGoogle Scholar
  55. Basketter DA, Casati S, Cronin MTD, Diembeck W, Gerberick GF, Hadgraft J, Kasting G, Marty JP, Nikolaidis E, Patlewicz G, Pease C, Roberts DW, Roggen E, Rovida C, van der Sandt J (2007c) Skin sensitisation and epidermal disposition. Altern Lab Anim 35(1):137–154PubMedGoogle Scholar
  56. Basketter DA, Darlenski R, Fluhr J (2008a) Skin irritation and sensitisation: mechanisms and new approaches for risk assessment. Skin Pharmacol Physiol 21(4):191–202PubMedGoogle Scholar
  57. Basketter DA, Clapp CJ, Safford BJ, Jowsey IR, McNamee PM, Ryan CA, Gerberick GF (2008b) Preservatives and skin sensitisation quantitative risk assessment: risk benefit considerations. Dermatitis 19(1):20–27PubMedGoogle Scholar
  58. Basketter DA, Kimber I (2009) Updating the skin sensitisation in vitro data assessment paradigm in 2009. J Appl Toxicol 29(6):545–550PubMedGoogle Scholar
  59. Battelle (2002) Revised AR binding assay protocol: androgen receptor competitive binding protocol using rat ventral prostate cytosol, SOP no. NHEERL-H/RTD/EB/VW/2002-03-000. In: Quality assurance project plan for work assignment 2-22, Development of Androgen Receptor Binding Data, prepared by Battelle for US environmental protection agency, endocrine disruptor screening program, contract no. 68-W-01-023Google Scholar
  60. Baylin SB, Ohm JE (2006) Epigenetic gene silencing in cancer—a mechanism for early oncogenic pathway addition? Nat Rev Cancer 6:107–116PubMedGoogle Scholar
  61. Benfenati E, Benigni R, DeMarini DM, Helma C, Kirkland D, Martin TM, Mazzatorta P, Ouedraogo-Arras G, Richard AM, Schilter B, Schoonen WGEJ, Snyder RD, Yang C (2009) Predictive models for carcinogenicity and mutagenicity: frameworks, state-of-the-art, and perspectives. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 27(2):57–90Google Scholar
  62. Benigni R, Bossa C (2008) Predictivity of QSAR. J Chem Inf Model 48:971–980PubMedGoogle Scholar
  63. Benigni R, Bossa C, Tcheremenskaia O, Giuliani A (2010) Alternatives to the carcinogenicity bioassay: in silico methods, and the in vitro and in vivo mutagenicity assays. Expert Opin Drug Metab Toxicol 6:809–819PubMedGoogle Scholar
  64. Bercu JP, Morton SM, Deahl JT, Gombar VK, Callis CM, van Lier RB (2010) In silico approaches to predicting cancer potency for risk assessment of genotoxic impurities in drug substances. Regul Toxicol and Pharmacol 57:300–306Google Scholar
  65. Bernillon P, Bois FY (2000) Statistical issues in toxicokinetic modeling: a Bayesian perspective. Environ Health Perspect 108:883–893PubMedGoogle Scholar
  66. Bernshausen T, Noss A, Boehn SN, Fabian E, Kamp HG, Kaufmann T, Koch M, Wessa P, van Ravenzwaay B, Landsiedel R (2009) Metabolic Competences of the Chicken Embryo used in the Toxicity Screening Test (CHEST) as an In Vitro Test System for Teratogenicity and Embryotoxicity. 50. Jahrestagung der DGPT, Mainz, GermanyGoogle Scholar
  67. Bérubé K, Aufderheide M, Breheny D, Clothier R, Combes R, Duffin R, Forbes B, Gaça M, Gray A, Hall I, Kelly M, Lethem M, Liebsch M, Merolla L, Morin JP, Seagrave JC, Swartz MA, Tetley TD, Umachandran M (2009) In Vitro Models of Inhalation Toxicity and Disease. The Report of a FRAME Workshop. Altern Lab Anim 37(1):89-141Google Scholar
  68. Bessems JGM (2009) Opinion on the usefulness of in vitro data for human risk assessment. Suggestions for better use of non-testing approaches. Letter report 320016002/2009 RIVM. Accessed 15 January 2011
  69. Billinton N, Hastwell PW, Beerens D, Birrell L, Ellis P, Maskell S, Webster TW, Windebank S, Woestenborghs F, Lynch AM, Scott AD, Tweats DJ, van Gompel J, Rees RW, Walmsley RM (2008) Interlaboratory assessment of the GreenScreen HC GADD45a-GFP genotoxicity screening assay: an enabling study for independent validation as an alternative method. Mutat Res 653:23–33PubMedGoogle Scholar
  70. Billinton N, Bruce S, Hansen JR, Hastwell PW, Jagger C, McComb C, Klug ML, Pant K, Rabinowitz A, Rees R, Tate M, Vinggaard AM, Walmsley RM (2010) A pre-validation transferability study of the GreenScreen HC GADD45a-GFP assay with a metabolic activation system (S9). Mutat Res 700:44–50PubMedGoogle Scholar
  71. Bitsch A, Jacobi S, Melber C, Wahnschaffe U, Simetska N, Mangelsdorf I (2006) REPDOSE: a database on repeated dose toxicity studies of commercial chemicals—a multifunctional tool. Regul Toxicol Pharmacol 46(3):202–210PubMedGoogle Scholar
  72. Bittner M, Hilscherova K, Giesy JP (2009) In vitro assessment of AhR-mediated activities of TCDD in mixture with humic substances. Chemosphere 76:1505–1508PubMedGoogle Scholar
  73. Blaauboer BJ (2002) The necessity of biokinetic information in the interpretation of in vitro toxicity data. Altern Lab Anim 30(suppl 2):85–91PubMedGoogle Scholar
  74. Blaauboer BJ (2003) The integration of data on physico-chemical properties, in vitro-derived toxicity data and physiologically based kinetic and dynamic modelling as a tool in hazard and risk assessment. A commentary. Toxicol Lett 138(1-2):161-171Google Scholar
  75. Blaauboer BJ (2008) The contribution of in vitro toxicity data in hazard and risk assessment: current limitations and future perspectives. Toxicol Lett 180(2):81–84PubMedGoogle Scholar
  76. Blaauboer BJ (2010) Biokinetic modeling and in vitro-in vivo extrapolations. J Toxicol Environ Health B Crit Rev 13(2–4):242–252PubMedGoogle Scholar
  77. Blaauboer BJ, Andersen ME (2007) The need for a new toxicity testing and risk analysis paradigm to implement REACH or any other large scale testing initiative. Arch Toxicol 81(5):385–387PubMedGoogle Scholar
  78. Blaauboer BJ, Bayliss MK, Castell JV, Evelo CTA, Frazier JM, Groen K, Gülden M, Guillouzo A, Hissink AM, Houston BJ, Johanson G, de Jongh J, Kedderis GL, Reinhardt CA, van de Sandt JJM, Semino G (1996) The use of biokinetics and in vitro methods in toxicological risk evaluation. ATLA 24:473–497Google Scholar
  79. Blaauboer BJ, Barratt MD, Houston BJ (1999) The integrated use of alternative methods in toxicological risk evaluation: ECVAM integrated testing strategies task force report 1. ATLA 27:229–237Google Scholar
  80. Blackburn K, Stickney JA, Carlson-Lynch HL, McGinnis PA, Chappell L, Felter SP (2005) Application of the threshold of toxicological concern approach to ingredients in personal and household care products. Regul Toxicol and Pharmacol 43:249–259Google Scholar
  81. Boehn SNE, Kaufmann T, Koch M, Wessa P, Kamp HG, Landsiedel R, van Ravenzwaay B (2009) Modification and evaluation of the chicken embryotoxicity screening test (CHEST) as in vitro test system for embryotoxicity. VII World Congress on Alternatives & Animal Use in the Life Sciences, RomeGoogle Scholar
  82. Boekelheide K, Campion SN (2010) Toxicity testing in the 21st century: using the new toxicity testing paradigm to create a taxonomy of adverse effects. Toxicol Sci 114(1):20–24PubMedGoogle Scholar
  83. Boess F, Kamber M, Romer S, Gasser R, Muller D, Albertini S, Suter L (2003) Gene expression in two hepatic cell lines, cultured primary hepatocytes, and liver slices compared to the in vivo liver gene expression in rats: possible implications for toxicogenomics use of in vitro systems. Toxicol Sci 73(2):386–402PubMedGoogle Scholar
  84. Böhme A, Thaens D, Paschke A, Schüürmann G (2009) Kinetic glutathione chemoassay to quantify thiol reactivity of organic electrophiles application to α,β-unsaturated ketones, acrylates, and propiolates. Chem Res Toxicol 22(4):742–750PubMedGoogle Scholar
  85. Bois FY, Paxman D (1992) An analysis of exposure rate effects for benzene using a physiologically based pharmacokinetic model. Regul Toxicol Pharmacol 15:122–136PubMedGoogle Scholar
  86. Bois FY, Smith T, Gelman A, Chang HY, Smith AE (1999) Optimal design for a study of butadiene toxicokinetics in humans. Toxicol Sci 49:213–224PubMedGoogle Scholar
  87. Bois FY, Jamei M, Clewell HJ (2010) PBPK modelling of inter-individual variability in the pharmacokinetics of environmental chemicals. Toxicology 278(3):256–267PubMedGoogle Scholar
  88. 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(10):781–792PubMedGoogle Scholar
  89. 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(2):87–96PubMedGoogle Scholar
  90. Boobis AR, Daston GP, Preston RJ, Olin SS (2009a) Application of key events analysis to chemical carcinogens and noncarcinogens. Crit Rev Food Sci Nutr 49(8):690–707PubMedGoogle Scholar
  91. Boobis AR, Cohen SM, Doerrer NG, Galloway SM, Haley PJ, Hard GC, Hess FG, Macdonald JS, Thibault S, Wolf DC, Wright J (2009b) A data-based assessment of alternative strategies for identification of potential human cancer hazards. Toxicol Pathol 37(6):714–732PubMedGoogle Scholar
  92. Boogaard PJ, Nagelkerke JF, Mulder GJ (1990) Renal proximal tubular cells in suspension or in primary culture as in vitro models to study nephrotoxicity. Chem Biol Interact.76(3):251-291Google Scholar
  93. Bouvier d’Yvoire M, Prieto P, Blaauboer BJ, Bois FY, Boobis A, Brochot C, Coecke S, Freidig A, Gundert-Remy U, Hartung T, Jacobs MN, Lav T, Leahy DE, Lennernäs H, Loizou GD, Meek B, Pease C, Rowland M, Spendiff M, Yang J, Zeilmaker M (2007) Physiologically-based kinetic modelling (PBK modelling): meeting the 3Rs agenda: the report and recommendations of ECVAM workshop 63. ATLA 35:661–671Google Scholar
  94. Bouwman T, Cronin MT, Bessems JG, van de Sandt JJ (2008) Improving the applicability of (Q)SARs for percutaneous penetration in regulatory risk assessment. Hum Exp Toxicol 27:269–276PubMedGoogle Scholar
  95. Brandenberger C, Rothen-Rutishauser B, Mühlfeld C, Schmid O, Ferron GA, Maier KL, Gehr P, Lenz AG (2010) Effects and uptake of gold nanoparticles deposited at the air–liquid interface of a human epithelial airway model. Toxicol Appl Pharmacol 242(1):56–65PubMedGoogle Scholar
  96. Brandon EF, Oomen AG, Rompelberg CJ, Versantvoort CH, van Engelen JG, Sips AJ (2006) Consumer product in vitro digestion model: bioaccessibility of contaminants and its application in risk assessment. Regul Toxicol Pharmacol 44:161–171PubMedGoogle Scholar
  97. Brannen KC, Panzica-Kelly JM, Danberry TL, Augustine-Rauch KA (2010) Development of a zebrafish embryo teratogenicity assay and quantitative prediction model. Birth Defects Res B Dev Reprod Toxicol 89:66–77PubMedGoogle Scholar
  98. Bremer S, Van Dooren M, Paparella M, Kossolov E, Fleischmann B, Hescheler J (1999) Establishment of an embryotoxicity assay with green fluorescence protein-expressing embryonic cell-derived cardiomyocytes. Atla Altern Lab Anim 27:471–484Google Scholar
  99. Bremer S, Pellizzer C, Hoffmann S, Seidle T, Hartung T (2007) The development of new concepts for assessing reproductive toxicity applicable to large scale toxicological programmes. Curr Pharm Des 13:3047–3058PubMedGoogle Scholar
  100. Brown NA, Fabro S (1981) Quantitation of rat embryonic development in vitro: a morphological scoring system. Teratology 24:65–78PubMedGoogle Scholar
  101. Brown NA, Spielmann H, Bechter R, Flint OP, Freeman SJ, Jelinek RJ, Koch E, Nau H, Newall DR, Palmer AK et al (1995) Screening chemicals for reproductive toxicity: the current alternatives; the report and recommendations of an ECVAM/ETS workshop (ECVAM workshop 12). Altern Lab Anim 23(6):868–882Google Scholar
  102. Broxmeyer HE, Srour E, Orschell C, Ingram DA, Cooper S, Plett PA, Mead LE, Yoder MC (2006) Cord blood stem and progenitor cells. Methods Enzymol 419:439–473PubMedGoogle Scholar
  103. Bucher JR (1998) Update on national toxicology program (NTP) assays with genetically altered or “transgenic” mice. Environ Health Perspect 106:619–621PubMedGoogle Scholar
  104. Buehler EV (1965) Delayed contact hypersensitivity in the guinea pig. Arch Dermatol 91:171–177PubMedGoogle Scholar
  105. Buesen R, Genschow E, Slawik B, Visan A, Spielmann H, Luch A, Seiler A (2009) Embryonic stem cell test remastered: comparison between the validated EST and the new molecular FACS-EST for assessing developmental toxicity in vitro. Toxicol Sci 108:389–400PubMedGoogle Scholar
  106. Busquet F, Nagel R, von Landenberg F, Mueller SO, Huebler N, Broschard TH (2008) Development of a new screening assay to identify proteratogenic substances using zebrafish Danio rerio embryo combined with an exogenous mammalian metabolic activation system (mDarT). Toxicol Sci 104:177–188PubMedGoogle Scholar
  107. Buzanska L, Sypecka J, Nerini-Molteni S, Compagnoni A, Hogberg HT, del Torchio R, Domanska-Janik K, Zimmer J, Coecke S (2009) A human stem cell-based model for identifying adverse effects of organic and inorganic chemicals on the developing nervous system. Stem Cells 27(10):2591–2601PubMedGoogle Scholar
  108. Caesar software (2010) Accessed 30 June 2010
  109. Carfí M, Gennari A, Malerba I, Corsini E, Pallardy M, Pieters R, Van Loveren H, Vohr HW, Hartung T, Gribaldo L (2007) In vitro tests to evaluate immunotoxicity: a preliminary study. Toxicology 229(1–2):11–22PubMedGoogle Scholar
  110. Carfí M, Bowe G, Ferrario D, Pieters R, Gribaldo L (2010) Maintenance and characterization of lymphocytes in human long term bone marrow cultures to study immunotoxicity. Toxicol In Vitro 24(5):1395–1403PubMedGoogle Scholar
  111. Carmichael P, Davies M, Dent M, Fentem J, Fletcher S, Gilmour N, MacKay C, Maxwell G, Merolla L, Pease C, Reynolds F, Westmoreland C (2009) Non-animal approaches for consumer safety risk assessments: unilever’s scientific research programme. Altern Lab Anim 37(6):595–610PubMedGoogle Scholar
  112. Carthew P, Clapp C, Gutsell S (2009) Exposure based waiving: the application of the toxicological threshold of concern (TTC) to inhalation exposure for aerosol ingredients in consumer products. Food Chem Toxicol 47:1287–1295PubMedGoogle Scholar
  113. Casati S, Aeby P, Basketter DA, Cavani A, Gennari A, Gerberick GF, Griem P, Hartung T, Kimber I, Lepoittevin JP, Meade BJ, Pallardy M, Rougier N, Rousset F, Rubinstenn G, Sallusto F, Verheyen GR, Zuang V (2005) Report and recommendations of ECVAM workshop 51. Dendritic cells as a tool for the predictive identification of skin sensitisation hazard. Altern Lab Anim 33(1):47–62Google Scholar
  114. Cecchelli R, Berezowski V, Lundquist S, Culot M, Renftel M, Dehouck MP, Fenart L (2007) Modelling of the blood–brain barrier in drug discovery and development. Nat Rev Drug Disc 6(8):650–661Google Scholar
  115. Cefic (2010) Accessed 30 June 2010
  116. Cezar GG, Quam JA, Smith AM, Rosa GJ, Piekarczyk MS, Brown JF, Gage FH, Muotri AR (2007) Identification of small molecules from human embryonic stem cells using metabolomics. Stem Cells Dev 16:869–882PubMedGoogle Scholar
  117. Chao P, Maguire T, Novik E, Cheng KC, Yarmush ML (2009) Evaluation of a microfluidic based cell culture platform with primari human hepatocytes for the prediction of hepatic. Biochem Pharmacol 78:625–632PubMedGoogle Scholar
  118. Chapin RE, Stedman DB (2009) Endless possibilities: stem cells and the vision for toxicology testing in the 21st century. Toxicol Sci 112(1):17–22PubMedGoogle Scholar
  119. Chapin R, Stedman D, Paquette J, Streck R, Kumpf S, Deng S (2007) Struggles for equivalence: in vitro developmental toxicity model evolution in pharmaceuticals in 2006. Toxicol In Vitro 21:1545–1551PubMedGoogle Scholar
  120. Chaudhry Q, Piclin N, Cotterill J, Pintore M, Price NR, Chrétien JR, Roncaglioni A (2010) Global QSAR models of skin sensitisers for regulatory purposes. Chem Cent J 4(suppl 1):S5PubMedGoogle Scholar
  121. Cheeseman MA, Machuga EJ, Bailey AB (1999) A tiered approach to threshold of regulation. Food Chem Toxicol 37:387–412PubMedGoogle Scholar
  122. Chipinda I, Ajibola RO, Morakinyo MK, Ruwona TB, Simoyi RH, Siegel PD (2010) Rapid and simple kinetics screening assay for electrophilic dermal sensitisers using nitrobenzenethiol. Chem Res Toxicol 23(5):918–925PubMedGoogle Scholar
  123. Choi S, Park SY, Jeong J, Cho E, Phark S, Lee M, Kwak D, Lim JY, Jung WW, Sul D (2010) Identification of toxicological biomarkers of di(2-ethylhexyl) phthalate in proteins secreted by HepG2 cells using proteomic analysis. Proteomics 10(9):1831–1846PubMedGoogle Scholar
  124. Clewell HJ, Tan YM, Campbell JL, Andersen ME (2008) Quantitative interpretation of human biomonitoring data. Toxicol Appl Pharmacol 231:122–133PubMedGoogle Scholar
  125. Coecke S, Rogiers V, Bayliss M, Castell J, Doehmer J, Fabre G, Fry J, Kern A, Westmoreland C (1999) The use of long-term hepatocyte cultures for detection induction of drug metabolising enzymes: the current status. ATLA 27:579–638Google Scholar
  126. Coecke S, Blaauboer BJ, Elaut G, Freeman S, Freidig A, Gensmantel N, Hoet P, Kapoulas VM, Ladstetter B, Langley G, Leahy D, Mannens G, Meneguz A, Monshouwer M, Nemery B, Pelkonen O, Pfaller W, Prieto P, Proctor N, Rogiers V, Rostami-Hodjegan A, Sabbioni E, Steiling W, van de Sandt JJ (2005) Toxicokinetics and metabolism. Altern Lab Anim 33(1):147–175PubMedGoogle Scholar
  127. Coecke S, Ahr H, Blaauboer BJ, Bremer S, Casati S, Castell J, Combes R, Corvi R, Crespi CL, Cunningham ML, Elaut G, Eletti B, Freidig A, Gennari A, Ghersi-Egea JF, Guillouzo A, Hartung T, Hoet P, Ingelman-Sundberg M, Munn S, Janssens W, Ladstetter B, Leahy D, Long A, Meneguz A, Monshouwer M, Morath S, Nagelkerke F, Pelkonen O, Ponti J, Prieto P, Richert L, Sabbioni E, Schaack B, Steiling W, Testai E, Vericat JA, Worth A (2006) Metabolism: a bottleneck in in vitro toxicological test development. The report and recommendations of ECVAM workshop 54. ATLA34(1):49–84Google Scholar
  128. Cohen SM (2004) Human carcinogenic risk evaluation: an alternative approach to the 2-year rodent bioassay. Toxicol Sci 80(2):225–229PubMedGoogle Scholar
  129. Combes R, Balls M, Illing P, Bhogal N, Dale J, Duv‚ G, Feron V, Grindon C, Gülden M, Loizou G, Priston R, Westmoreland C (2006) Possibilities for a new approach to chemicals risk assessment. The report of a FRAME workshop. Altern Lab Anim 34(6):621–649Google Scholar
  130. Conolly RB, Butterworth BE (1995) Biologically based dose response model for hepatic toxicity: a mechanistically based replacement for traditional estimates of noncancer risk. Toxicol Lett 82–83:901–906PubMedGoogle Scholar
  131. Constant S (2010) Assessment of acute, long-term and chronic respiratory toxicity using a long shelf-life 3D model of the human airway epithelium. ALTEX 27(suppl 2/10):29Google Scholar
  132. Contrera JF, Matthews EJ, Kruhlak NL, Benz RD (2004) Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modelling of the human maximum recommended daily dose. Regul Toxicol Pharmacol 40(3):185–206PubMedGoogle Scholar
  133. Contrera JF, Kruhlak NL, Matthews EJ, Benz RD (2007) Comparison of MC4PC and MDL-QSAR rodent carcinogenicity predictions and the enhancement of predictive performance by combining QSAR models. Regul Toxicol Pharmacol 49:172–182PubMedGoogle Scholar
  134. Cooper RL, Lamb JC, Barlow SM, Bentley K, Brady AM, Doerrer NG, Eisenbrandt DL, Fenner-Crisp PA, Hines RN, Irvine LF, Kimmel CA, Koeter H, Li AA, Makris SL, Sheets LP, Speijers G, Whitby KE (2006) A tiered approach to life stages testing for agricultural chemical safety assessment. Crit Rev Toxicol 36:69–98PubMedGoogle Scholar
  135. Cordelli E, Fresegna AM, D’Alessio A, Eleuteri P, Spano M, Pacchierotti F, Villani P (2007) ReProComet: a new in vitro method to assess DNA damage in mammalian sperm. Toxicol Sci 99:545–552PubMedGoogle Scholar
  136. Corsini E, Mitjans M, Galbiati V, Lucchi L, Galli CL, Marinovich M (2009) Use of IL-18 production in a human keratinocyte cell line to discriminate contact sensitisers from irritants and low molecular weight respiratory allergens. Toxicol In Vitro 23(5):789–796PubMedGoogle Scholar
  137. Corvi R, Albertini S, Hartung T, Hoffmann S, Maurici D, Pfuhler S, van Benthem J, Vanparys P (2008) ECVAM retrospective validation of in vitro micronucleus test (MNT). Mutagenesis 23:271–283PubMedGoogle Scholar
  138. Cramer GM, Ford RA, Hall RL (1978) Estimation of toxic hazard—a decision tree approach. Food Cosmet Toxicol 16:255–276PubMedGoogle Scholar
  139. Crean D, Aschauer L, Jennings P, Leonard M (2010) Toxicity profiling of nephrotoxins in the human proximal tubular RPTEC-TERT1 cell line: influence of hypoxia. ALTEX 27(suppl 2/10):31Google Scholar
  140. Creton S, Billington R, Davies W, Dent MP, Hawksworth GM, Parry S, Travis KZ (2009) Application of toxicokinetics to improve chemical risk assessment: implications for the use of animals. Regul Toxicol Pharmacol 55(3):291–299PubMedGoogle Scholar
  141. Crivori P, Poggesi I (2006) Computational approaches for predicting CYP-related metabolism properties in the screening of new drugs. Eur J Med Chem 41(7):795–808PubMedGoogle Scholar
  142. Cronin MTD, Hewitt M (2007) In silico models to predict passage through the skin and other barriers. In: Testa B, van de Waterbeemd H (eds) Comprehensive medicinal chemistry II. Elsevier, Oxford, pp 725–744Google Scholar
  143. Cronin MTD, Worth AP (2008) (Q)SARs for predicting effects relating to reproductive toxicity. Qsar Combinat Sci 27:91–100Google Scholar
  144. Curren RD, Southee JA, Spielmann H, Liebsch M, Fentem JH, Balls M (1995) The role of pre-validation in the development, validation and acceptance of alternative methods. Altern Lab Anim 23:211–217Google Scholar
  145. Curren RD, Mun GC, Gibson DP, Aardema MJ (2006) Development of a method for assessing micronucleus induction in a 3D human skin model EpiDermTM. Mutat Res 607:192–204PubMedGoogle Scholar
  146. Dahl SG, Aarons L, Gundert-Remy U, Karlsson MO, Schneider YJ, Steimer JL, Troc¢niz IF (2010) Incorporating physiological and biochemical mechanisms into pharmacokinetic-pharmacodynamic models: a conceptual framework. Basic Clin Pharmacol Toxicol 106:2–12PubMedGoogle Scholar
  147. Davies M, Pendlington RU, Page L, Roper CS, Sanders DJ, Bourner C, Pease CK, Mackay C (2010) Determining epidermal disposition kinetics for use in an integrated non-animal approach to skin sensitisation risk assessment. Toxicol Sci kfq326v1–kfq326Google Scholar
  148. De Bruyn AMH, Gobas FAPC (2007) The sorptive capacity of animal protein. Environ Toxicol Chem 26:1803–1808Google Scholar
  149. De Buck SS, Sinha VK, Fenu LA, Gilissen RA, Mackie CE, Nijsen MJ (2007) The prediction of drug metabolism, tissue distribution, and bioavailability of 50 structurally diverse compounds in rat using mechanism-based absorption, distribution, and metabolism prediction tools. Drug Metab Dispos 35:649–659PubMedGoogle Scholar
  150. De Gottardi A, Vinciguerra M, Sgroi A, Moukil M, Ravier-Dall’Antonia F, Pazienza V, Pugnale P, Foti M, Hadengue A (2007) Microarray analyses and molecular profiling of steatosis induction in immortalized human hepatocytes. Lab Invest 87(8):792–806PubMedGoogle Scholar
  151. de Graaf C, Vermeulen NP, Feenstra KA (2005) Cytochrome P450 in silico: an integrative modeling approach. J Med Chem 48(8):2725–2755PubMedGoogle Scholar
  152. De Kock J, Vanhaecke T, Biernaskie JA, Rogiers V, Snykers S (2009) Characterization and hepatic differentiation of skin-derived precursors from adult foreskin by sequential exposure to hepatogenic cytokines and growth factors reflecting liver development. Toxicol In Vitro 23(8):1522–1527PubMedGoogle Scholar
  153. de Longueville F, Atienzar FA, Marcq L, Dufrane S, Evrard S, Wouters L, Leroux F, Bertholet V, Gerin B, Whomsley R, Arnould T, Remacle J, Canning M (2003) Use of a low-density microarray for studying gene expression patterns induced by hepatotoxicants on primary cultures of rat hepatocytes. Toxicol Sci 75(2):378–392PubMedGoogle Scholar
  154. De Vries A, van Steeg H, Opperhuizen A (2004) Transgenic mice as alternatives in carcinogenicity testing: current status. RIVM report 340700001Google Scholar
  155. Dearden JC, Barratt MD, Benigni R, Bristol DW, Combes RD, Cronin MTD, Judson PN, Payne MP, Richard AM, Tichy M, Worth AP, Yourick JJ (1997) The development and validation of expert systems for predicting toxicity. Altern Lab Anim 25:223–252Google Scholar
  156. DeJongh J, Forsby A, Houston JB, Beckman M, Combes R, Blaauboer BJ (1999a) An integrated approach to the prediction of systemic toxicity using computer-based biokinetic models and biological in vitro test methods: overview of a prevalidation study based on the ECITTS project. Toxicol In Vitro 13:549–554PubMedGoogle Scholar
  157. DeJongh J, Nordin-Andersson M, Ploeger BA, Forsby A (1999b) Estimation of systemic toxicity of acrylamide by integration on in vitro toxicity data with kinetic simulations. Toxicol Appl Pharmacol 158(3):261–268PubMedGoogle Scholar
  158. Deschl U, Vogel J, Aufderheide M (2010) Development of an in vitro exposure model for investigating the biological effects of therapeutic aerosols on human cells from the respiratory tract. Exp Toxicol Pathol. doi: 10.1016/j.etp.2010.04.013
  159. Devillers J (2009) Endocrine disruption modeling. CRC Press, Boca RatonGoogle Scholar
  160. DiPaolo JA, Donovan P, Nelson R (1969) Quantitative studies of in vitro transformation by chemical carcinogens. J Natl Cancer Inst 42:867–874PubMedGoogle Scholar
  161. Divkovic M, Pease CM, Gerberick GF, Basketter DA (2005) Hapten-protein binding: from theory to practical application in the in vitro prediction of skin sensitisation. Contact Derm 53(4):189–200PubMedGoogle Scholar
  162. Donato MT, Martínez-Romero A, Jiménez N, Negro A, Herrera G, Castell JV, O’Connor JE, Gómez-Lechón MJ (2009) Cytometric analysis for drug-induced steatosis in HepG2 cells. Chem Biol Interact 181(3):417–423PubMedGoogle Scholar
  163. Doull J, Cattley R, Elcombe C, Lake BG, Swenberg J, Wilkinson C, Williams G, van Gemert M (1999) A cancer risk assessment of di(2-ethylhexyl) phthalate: application of the new US EPA risk assessment guidelines. Regul Toxicol Pharmacol 29:327–357PubMedGoogle Scholar
  164. Dr. Hadwen Trust Science Review (2006) Showcasing successes in non-animal research. In Dr. Hadwen Trust Science Review. Dr. Hadwen Trust.
  165. Durmus E, Inan O, Celik I, Sur E, Ozkan Y, Acar A, Aydin MF (2005) Use of the fertilized hen’s egg in the evaluation of embryotoxicity of dental alloys. J Biomed Mater Res B Appl Biomater 72:322–327PubMedGoogle Scholar
  166. 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 26:461–473PubMedGoogle Scholar
  167. ECHA (2008) Guidance on information requirements and chemical safety assessment. Chapter R.7a: endpoint specific guidance Accessed 15 Jan 2011
  168. ECHA (2010) Practical guide on how to report categories and read-across.
  169. Edginton AN, Theil FP, Schmitt W, Willmann S (2008) Whole body physiologically-based pharmacokinetic models: their use in clinical drug development. Expert Opin Drug Metab Toxicol 4:1143–1152PubMedGoogle Scholar
  170. EFSA, European Food Safety Authority (2004) Scientific panel on food additives, flavourings, processing aids and materials in contact with food. Opinion on flavouring group FGE.03 Acetals of branched- and straight-chain aliphatic saturated primary alcohols and branched- and straight-chain saturated aldehydes, and an orthoester of formic acid, from chemical groups 1 and 2. Opinion expressed on 7 Oct 2004.
  171. EFSA, European Food Safety Authority (2009) Report of the PPR Unit on the outcome of the public consultation on the revision of the existing guidance document on dermal absorption scientific opinion on the revision of the guidance document on dermal absorptionGoogle Scholar
  172. El-Ali J, Sorger PK, Jensen KF (2006) Cells on chips. Nature 442:403–411PubMedGoogle Scholar
  173. Elaut G, Henkens T, Papeleu P, Snykers S, Vinken M, Vanhaecke T, Rogiers V (2006) Molecular mechanisms underlying the dedifferentiation process of isolated hepatocytes and their cultures. Curr Drug Metab 7(6):629–660PubMedGoogle Scholar
  174. Elferink MG, Olinga P, Draaisma AL, Merema MT, Bauerschmidt S, Polman J, Schoonen WG, Groothuis GM (2008) Microarray analysis in rat liver slices correctly predicts in vivo hepatotoxicity. Toxicol Appl Pharmacol 229(3):300–309PubMedGoogle Scholar
  175. 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 637:23–39PubMedGoogle Scholar
  176. Ellinger-Ziegelbauer H, Aubrecht J, Kleinjans JC, Ahr HJ (2009a) Application of toxicogenomics to study mechanisms of genotoxicity and carcinogenicity. Toxicol Lett 186:36–44PubMedGoogle Scholar
  177. Ellinger-Ziegelbauer H, Fostel JM, Aruga C, Bauer D, Boitier E, Deng S, Dickinson D, Le Fevre AC, Fornace AJ Jr, Grenet O, Gu Y, Hoflack JC, Shiiyama M, Smith R, Snyder RD, Spire C, Tanaka G, Aubrecht J (2009b) Characterization and interlaboratory comparison of a gene expression signature for differentiating genotoxic mechanisms. Toxicol Sci 10:341–352Google Scholar
  178. EMEA (2006) European medicines evaluation agency. Committee for medicinal products for human use (CHMP). Guideline on the limits of genotoxic impurities. CPMP/SWP/5199/02. London, 28 June 2006. EMEA/CHMP/QWP/251344/2006.
  179. EMEA (2008) Committee for medicinal products for human use (CHMP). Questions & answers on the CHMP guideline on the limits of genotoxic impurities. Rev 1. London, 26 June 2008. Doc.Ref. EMEA/CHMP/SWP/431994/2007Google Scholar
  180. Emter R, Ellis G, Natsch A (2010) Performance of a novel keratinocyte-based reporter cell line to screen skin sensitisers in vitro. Toxicol Appl Pharmacol 245(3):281–290PubMedGoogle Scholar
  181. Enoch SJ, Cronin MTD (2010) A review of the electrophilic reaction chemistry involved in covalent DNA binding. Crit Rev Toxicol 40:728–748PubMedGoogle Scholar
  182. Enoch SJ, Madden JC, Cronin MT (2008) Identification of mechanisms of toxic action for skin sensitisation using a SMARTS pattern based approach. SAR QSAR Environ Res 19(5–6):555–578PubMedGoogle Scholar
  183. Enoch SJ, Cronin MTD, Madden JC, Hewitt M (2009) Formation of structural categories to allow for read-across for teratogenicity. QSAR Combinat Sci 28:696–708Google Scholar
  184. Enslein K, Gombar VK, Blake BW (1994) International commission for protection against environmental mutagens and carcinogens. Use of SAR in computer-assisted prediction of carcinogenicity and mutagenicity of chemicals by the TOPKAT program. Mutat Res 205:47–61Google Scholar
  185. Eriksson L, Jaworska JS, Worth AP, Cronin MTD, McDowell RM, Gramatica P (2003) Methods for reliability, uncertainty assessment, and applicability evaluations of classification and regression based QSARs. Environmental Health Perspectives 22:1361–1375
  186. Escher SE, Tluczkiewicz I, Batke M, Bitsch A, Melber C, Kroese ED, Buist HE, Mangelsdorf I (2010) Evaluation of inhalation TTC values with the database RepDose. Regul Toxicol Pharmacol 58:259–274PubMedGoogle Scholar
  187. Eskes C, Zuang V (2005) Alternative (non-animal) methods for cosmetics testing: current status and future prospects. A report prepared in the context of the 7th amendment of the cosmetics directive for establishing the timetable for phasing out animal testing. ATLA 33(suppl 1):19–20Google Scholar
  188. Esteller M (2007) Cancer epigenomics. DNA methylomes and histone-modification maps. Nat Rev Genet 8:286–298PubMedGoogle Scholar
  189. EU (1976) Council directive 76/768/EEC of July 1976 on the approximation of the laws of the member states relating to cosmetic products. Off J L262:169–200Google Scholar
  190. EU (2003) Directive 2003/15/EC of the European parliament and the council of 27 February 2003 amending council directive 76/768/EEC on the approximation of the laws of the members states relating to cosmetic products. Off J Eur Union L66:26–35Google Scholar
  191. EU (2008) Council regulation 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). Off J Eur Union L142:1–739Google Scholar
  192. Fabjan E, Hulzebos E, Mennes W, Piersma AH (2006) A category approach for reproductive effects of phthalates. Crit Rev Toxicol 36:695–726PubMedGoogle Scholar
  193. Farkas D, Shader RI, von Moltke LL, Greenblatt DJ (2008) Mechanisms and consequences of drug-drug interactions. In: Gad SC (ed) Preclinical development handbook: ADME and biopharmaceutical properties, chapter 25. Wiley, New York, pp 879–918Google Scholar
  194. Fawcett DW, Leak LV, Heidger PM Jr (1970) Electron microscopic observations on the structural components of the blood-testis barrier. J Reprod Fert Suppl 10:105–122Google Scholar
  195. Felter SP, Robinson MK, Basketter DA, Gerberick GF (2002) A review of the scientific basis for uncertainty factors for use in quantitative risk assessment for the induction of allergic contact dermatitis. Contact Derm 47(5):257–266PubMedGoogle Scholar
  196. Felter SP, Ryan CA, Basketter DA, Gilmour NJ, Gerberick GF (2003) Application of the risk assessment paradigm to the induction of allergic contact dermatitis. Regul Toxicol Pharmacol 37(1):1–10PubMedGoogle Scholar
  197. Felter SP, Lane RW, Latulippe ME, Llewellyn GC, Olin SS, Scimeca JA, Trautman TD (2009) Refining the threshold of toxicological concern (TTC) for risk prioritization of trace chemicals in food. Food Chem Toxicol 47:2236–2245PubMedGoogle Scholar
  198. Ferrari T, Gini G (2010) An open source multistep model to predict mutagenicity from statitistical analysis and relevant structural alerts. Chem Cent J 4(suppl 1):S2.
  199. 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 99:90–100PubMedGoogle Scholar
  200. Fielden MR, Nie A, McMillian M, Elangbam CS, Trela BA, Yang Y, Dunn RT, Dragan Y, Fransson-Stehen R, Bogdanffy M, Adams SP, Foster WR, Chen SJ, Rossi P, Kasper P, Jacobson-Kram D, Tatsuoka KS, Wier PJ, Gollub J, Halbert DN, Roter A, Young JK, Sina JF, Marlowe J, Martus HJ, Aubrecht J, Olaharski AJ, Roome N, Nioi P, Pardo I, Snyder R, Perry R, Lord P, Mattes W, Car BD (2008) Interlaboratory evaluation of genomic signatures for predicting carcinogenicity in the rat. Toxicol Sci 103:28–34PubMedGoogle Scholar
  201. Fjodorova N, Vracko M, Novic M, Roncaglioni A, Benfenati E (2010) New public QSAR model for carcinogenicity. Chem Cent J 4(suppl 1):S3PubMedGoogle Scholar
  202. Flint OP (1983) A micromass culture method for rat embryonic neural cells. J Cell Sci 61:247–262PubMedGoogle Scholar
  203. Flint OP, Orton TC (1984) An in vitro assay for teratogens with cultures of rat embryo midbrain and limb bud cells. Toxicol Appl Pharmacol 76:383–395PubMedGoogle Scholar
  204. Fort JD, Paul RRP (2002) Enhancing the predictive validity of frog embryo teratogenesis assay—xenopus (FETAX). J Appl Toxicol 22:185–191PubMedGoogle Scholar
  205. Fowler P, Smith K, Jong J, Jeffrey L, Kirkland D, Pfuhler S, Carmichael P (in preparation) Reduction of misleading (false) positive results in mammalian genotoxicity assays. I. Choice of cell type. Mutat ResGoogle Scholar
  206. Franchini JL, Propst JT, Comer GR, Yost MJ (2007) Novel tissue engineered tubular heart tissue for in vitro pharmaceutical toxicity testing. Microsc Microanal 13(4):267–271PubMedGoogle Scholar
  207. Frankild S, Vølund A, Wahlberg JE, Andersen KE (2000) Comparison of the sensitivities of the Buehler test and the guinea pig maximization test for predictive testing of contact allergy. Acta Derm Venereol 80(4):256–262PubMedGoogle Scholar
  208. Frankos VH (1985) FDA perspectives on the use of teratology data for human risk assessment. Fundam Appl Toxicol 5:615–625PubMedGoogle Scholar
  209. Freyberger A, Weimer M, Tran HS, Ahr HJ (2009a) Assessment of a recombinant androgen receptor binding assay: initial steps towards validation. Reprod Toxicol 30(1):2–8PubMedGoogle Scholar
  210. Freyberger A, Witters H, Weimer M, Lofink W, Berckmans P, Ahr HJ (2009b) Screening for (anti)androgenic properties using a standard operation protocol based on the human stably transfected androgen sensitive PALM cell line. First steps towards validation. Reprod Toxicol 30(1):9–17PubMedGoogle Scholar
  211. Freyberger A, Wilson V, Weimer M, Tan S, Tran HS, Ahr HJ (2010) Assessment of a robust model protocol with accelerated throughput for a human recombinant full length estrogen receptor-alpha binding assay: protocol optimization and intralaboratory assay performance as initial steps towards validation. Reprod Toxicol 30(1):50–59PubMedGoogle Scholar
  212. Galvão dos Santos G, Reinders J, Ouwehand K, Rustemeyer T, Scheper RJ, Gibbs S (2009) Progress on the development of human in vitro dendritic cell based assays for assessment of the sensitising potential of a compound. Toxicol Appl Pharmacol 236(3):372–382PubMedGoogle Scholar
  213. Garberg P, Ball M, Borg N, Cecchelli R, Fenart L, Hurst RD, Lindmark T, Mabondzo A, Nilsson JE, Raub TJ, Stanimirovic D, Terasaki T, Oberg JO, Osterberg T (2005) In vitro models for the blood–brain barrier. Toxicol In Vitro 19(3):299–334PubMedGoogle Scholar
  214. Garcia-Domenech R, de Julian-Ortiz JV, Besalu E (2006) True prediction of lowest observed adverse effect levels. Mol Divers 10(2):159–168PubMedGoogle Scholar
  215. Gargas ML, Burgess RJ, Voisard DE, Cason GH, Andersen ME (1989) Partition coefficients of low-molecular-weight volatile chemicals in various liquids and tissues. Toxicol Appl Pharmacol 98:87–99PubMedGoogle Scholar
  216. Gelman A, Bois F, Jiang JM (1996) Physiological pharmacokinetic analysis using population modeling and informative prior distributions. J Am Stat Assoc 91:1400–1412Google Scholar
  217. Genschow E, Spielmann H, Scholz G, Seiler A, Brown N, Piersma A, Brady M, Clemann N, Huuskonen H, Paillard F, Bremer S, Becker K (2002) The ECVAM international validation study on in vitro embryotoxicity tests: results of the definitive phase and evaluation of prediction models. European centre for the validation of alternative methods. Altern Lab Anim 30:151–176PubMedGoogle Scholar
  218. Georgopoulos PG, Roy A, Gallo MA (1994) Reconstruction of short-term multi-route exposure to volatile organic compounds using physiologically based pharmacokinetic models. J Expo Anal Environ Epidemiol 4:309–328Google Scholar
  219. Gerberick GF, Robinson MK, Felter SP, White IR, Basketter DA (2001) Understanding fragrance allergy using an exposure-based risk assessment approach. Contact Derm 45(6):333–340PubMedGoogle Scholar
  220. Gerberick GF, Vassallo JD, Bailey RE, Chaney JG, Morrall SW, Lepoittevin JP (2004) Development of a peptide reactivity assay for screening contact allergens. Toxicol Sci 81(2):332–343PubMedGoogle Scholar
  221. Gerberick GF, Vassallo JD, Foertsch LM, Price BB, Chaney JG, Lepoittevin JP (2007) Quantification of chemical peptide reactivity for screening contact allergens: a classification tree model approach. Toxicol Sci 97(2):417–427PubMedGoogle Scholar
  222. Gerberick F, Aleksic M, Basketter D, Casati S, Karlberg AT, Kern P, Kimber I, Lepoittevin JP, Natsch A, Ovigne JM, Rovida C, Sakaguchi H, Schultz T (2008) Chemical reactivity measurement and the predictive identification of skin sensitisers. Altern Lab Anim 36(2):215–242PubMedGoogle Scholar
  223. Gerberick GF, Troutman JA, Foertsch LM, Vassallo JD, Quijano M, Dobson RL, Goebel C, Lepoittevin JP (2009) Investigation of peptide reactivity of prohapten skin sensitisers using a peroxidase-peroxide oxidation system. Toxicol Sci 112(1):164–174PubMedGoogle Scholar
  224. Gerlowski LE, Jain RK (1983) Physiologically based pharmacokinetic modeling: principles and applications. J Pharmacol Sci 72:1103–1127Google Scholar
  225. Ghisari M, Bonefeld-Jorgensen EC (2009) Effects of plasticizers and their mixtures on estrogen receptor and thyroid hormone functions. Toxicol Lett 189:67–77PubMedGoogle Scholar
  226. Gibaldi M, Perrier D (1982) Pharmacokinetics, 2nd edn, revised and expanded ed. Marcel Dekker, New YorkGoogle Scholar
  227. Gibbs S, van de Sandt JJ, Merk HF, Lockley DJ, Pendlington RU, Pease CK (2007) Xenobiotic metabolism in human skin and 3D human skin reconstructs: a review. Curr Drug Metab 8(8):758–772PubMedGoogle Scholar
  228. Gilani SH, Alibhai Y (1990) Teratogenicity of metals to chick embryos. J Toxicol Environ Health 30:23–31PubMedGoogle Scholar
  229. Gminski R, Tang T, Mersch-Sundermann V (2010) Cytotoxicity and genotoxicity in human lung epithelial A549 cells caused by airborne volatile organic compounds emitted from pine wood and oriented strand boards. Toxicol Lett 196(1):33–41PubMedGoogle Scholar
  230. Gold LS, Manley NB, Slone TH, Garfinkel GB, Ames BN, Rohrbach L, Stern BR, Chow K (1995) Sixth plot of the carcinogenic potency database: results of animal bioassays published in the general literature 1989–1990 and by the national toxicology program 1990–1993. Environ Health Perspect 103(suppl 8):3–122PubMedGoogle Scholar
  231. Gómez-Lechón MJ, Donato MT, Castell JV, Jover R (2003) Human hepatocytes as a tool for studying toxicity and drug metabolism. Curr Drug Metab 4(4):292–312PubMedGoogle Scholar
  232. Gómez-Lechón MJ, Castell JV, Donato MT (2008) An update on metabolism studies using human hepatocytes in primary culture. Expert Opin Drug Metab Toxicol 4(7):837–854PubMedGoogle Scholar
  233. Greim H, Arand M, Autrup H, Bolt HM, Bridges J, Dybing E, Glomot R, Foa V, Schulte-Hermann R (2006) Toxicological comments to the discussion about REACH. Arch Toxicol 80(3):121–124PubMedGoogle Scholar
  234. Griem P, Goebel C, Scheffler H (2003) Proposal for a risk assessment methodology for skin sensitisation based on sensitisation potency data. Regul Toxicol Pharmacol 38(3):269–290PubMedGoogle Scholar
  235. Griffiths CE, Dearman RJ, Cumberbatch M, Kimber I (2005) Cytokines and Langerhans cell mobilisation in mouse and man. Cytokine 32(2):67–70PubMedGoogle Scholar
  236. Grindon C, Combes R, Cronin MT, Roberts DW, Garrod JF (2006) Integrated testing strategies for use in the EU REACH system. Altern Lab Anim 34(4):407–427PubMedGoogle Scholar
  237. Grindon C, Combes R, Cronin MT, Roberts DW, Garrod JF (2008) An integrated decision-tree testing strategy for repeat dose toxicity with respect to the requirements of the EU REACH legislation. Altern Lab Anim 36(suppl 1):93–101PubMedGoogle Scholar
  238. Gubbels-van Hal WM, Blaauboer BJ, Barentsen HM, Hoitink MA, Meerts IA, van der Hoeven JC (2005) An alternative approach for the safety evaluation of new and existing chemicals, an excersise in integrated testing. Regul Toxicol Pharmacol 42(3):284–295PubMedGoogle Scholar
  239. Guguen-Guillouzo C, Corlu A, Guillouzo A (2010) Stem cell-derived hepatocytes and their use in toxicology. Toxicology 270(1):3–9PubMedGoogle Scholar
  240. Guironnet G, Dalbiez-Gauthier C, Rousset F, Schmitt D, Peguet-Navarro J (2000) In vitro human T cell sensitisation to haptens by monocyte-derived dendritic cells. Toxicol In Vitro 14(6):517–522PubMedGoogle Scholar
  241. Gülden M, Seibert H (2003) In vitro-in vivo extrapolation: estimation of human serum concentrations of chemicals equivalent cytotoxic concentrations in vitro. Toxicology 189:211–222PubMedGoogle Scholar
  242. Gülden M, Mörchel S, Seibert H (2001) Factors influencing nominal effective concentrations of chemical compounds in vitro: cell concentration. Toxicol In Vitro 15:233–243PubMedGoogle Scholar
  243. Guo L, Lobenhofer EK, Wang C, Shippy R, Harris SC, Zhang L, Mei N, Chen T, Herman D, Goodsaid FM, Hurban P, Philips KL, Deng QuJ, Sun YA X, Tong W, Dragon WT, Shi L (2006) Rat toxicogenomic study reveals analytical consistency across microarray platforms. Nat Biotechnol 24:1162–1169PubMedGoogle Scholar
  244. Guyton KZ, Kyle AD, Aubrecht J, Cogliano VJ, Eastmond DA, Jackson M, Keshava N, Sandy MS, Sonawane B, Zhang L, Waters MD, Smith MT (2009) Improving prediction of chemical carcinogenicity by considering multiple mechanisms and applying toxicogenomic approaches. Mutat Res 681:230–240PubMedGoogle Scholar
  245. Hah SS (2009) Recent advances in biomedical applications of accelerator mass spectrometry. J Biomed Sci 16:54. doi: 10.1186/1423-0127-16-54 PubMedGoogle Scholar
  246. Hallier-Vanuxeem D, Prieto P, Culot M, Diallo H, Landry C, Tati H, Cecchelli R (2009) New strategy for altering central nervous system toxicity: integration of blood brain barrier toxicity and permeability in neurotoxicity assessment. Toxicol In Vitro 23:447–453PubMedGoogle Scholar
  247. Harry GJ, Billingsley M, Bruinink A, Campbell IL, Classen W, Dorman DC, Galli C, Ray D, Smith RA, Tilson HA (1998) In vitro techniques for the assessment of neurotoxicity. Environ Health Perspect 106(suppl 1):131–158PubMedGoogle Scholar
  248. Hartig PC, Cardon MC, Blystone CR, Gray LE Jr, Wilson VS (2008) High throughput adjustable 96-well plate assay for androgen receptor binding: a practical approach for EDC screening using the chimpanzee AR. Toxicol Lett 181:126–131PubMedGoogle Scholar
  249. Hartung T, Bremer S, Casati S, Coecke S, Corvi R, Fortaner S, Gribaldo L, Halder M, Hoffmann S, Roi AJ, Prieto P, Sabbioni E, Scott L, Worth A, Zuang V (2004) A modular approach to the ECVAM principles on test validity. Altern Lab Anim 32:467–472Google Scholar
  250. 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 607:160–175PubMedGoogle Scholar
  251. Hattis D, Chu M, Rahmioglu N, Goble R, Verma P, Hartman K, Kozlak M (2008) A preliminary operational classification system for nonmutagenic modes of action for carcinogenesis. Critical Rev Toxicol 10:97–138Google Scholar
  252. Hauser C, Katz SI (1990) Generation and characterization of T-helper cells by primary in vitro sensitisation using Langerhans cells. Immunol Rev 117:67–84PubMedGoogle Scholar
  253. Hawksworth GM (2005) Isolation and culture of human renal cortical cells with characteristics of proximal tubules. Methods Mol Med 107:283–290PubMedGoogle Scholar
  254. Hayden P, Letasiova S, Kandarova H, Jackson G, Klausner M (2010) Development of a vapour cup dosing method for evaluation of chemical toxicity in the EpiAirwayTM organotypic in vitro human airway model: an animal alternative model for inhalation toxicity evaluation. ALTEX 27(suppl 2/10):52Google Scholar
  255. Helma C (2006) Lazy structure–activity relationships (lazar) for the prediction of rodent carcinogenicity and salmonella mutagenicity. Mol Divers 10:147–158PubMedGoogle Scholar
  256. Henkens T, Papeleu P, Elaut G, Vinken M, Rogiers V, Vanhaecke T (2007) Trichostatin A, a critical factor in maintaining the functional differentiation of primary cultured rat hepatocytes. Toxicol Appl Pharmacol 218(1):64–71PubMedGoogle Scholar
  257. Heringa MB, Schreurs RHMM, Busser F, van der Saag PT, van der Burg B, Hermens JL (2004) Towards more useful in vitro toxicity data with measured free concentrations. Environ Sci Technol 38:6263–6270PubMedGoogle Scholar
  258. Hernández 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 682:94–109PubMedGoogle Scholar
  259. Hernández LG, Slob W, van Steeg H, van Benthem J (submitted) Carcinogen risk assessment using in vivo genotoxicity data and the benchmark dose approach. Environ Mol MutagenGoogle Scholar
  260. Hewitt NJ, Lechón MJ, Houston JB, Hallifax D, Brown HS, Maurel P, Kenna JG, Gustavsson L, Lohmann C, Skonberg C, Guillouzo A, Tuschl G, Li AP, LeCluyse E, Groothuis GM, Hengstler JG (2007a) Primary hepatocytes: current understanding of the regulation of metabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism, enzyme induction, transporter, clearance, and hepatotoxicity studies. Drug Metab Rev 39(1):159–234PubMedGoogle Scholar
  261. Hewitt M, Madden JC, Rowe PH, Cronin MT (2007b) Structure-based modelling in reproductive toxicology: (Q)SARs for the placental barrier. SAR QSAR Environ Res 18:57–76PubMedGoogle Scholar
  262. Hewitt M, Ellison CM, Enoch SJ, Madden JC, Cronin MTD (2010) Integrating (Q)SAR models, expert systems and read-across approaches for the prediction of developmental toxicity. Reprod Toxicol 30(1):147–160PubMedGoogle Scholar
  263. Hirota M, Suzuki M, Hagino S, Kagatani S, Sasaki Y, Aiba S, Itagaki H (2009) Modification of cell-surface thiols elicits the activation of human monocytic cell line THP-1: possible involvement in the effect of haptens, 2–4 dinitrochlorobenzene and nickel sulfate. J Toxicol Sci 34(2):139–150PubMedGoogle Scholar
  264. Hooyberghs J, Schoeters E, Lambrechts N, Nelissen I, Witters H, Schoeters G, Van Den Heuvel R (2008) A cell-based in vitro alternative to identify skin sensitisers by gene expression. Toxicol Appl Pharmacol 231(1):103–111PubMedGoogle Scholar
  265. Houck KA, Kavlock RJ (2008) Understanding mechanisms of toxicity: insights from drug discovery research. Toxicol Appl Pharmacol 227(2):163–178PubMedGoogle Scholar
  266. House RV, Thomas PT (1995) In vitro induction of cytotoxic T lymphocytes. In: Burleson GR, Dean JH, Munson AE (eds) Methods in immunotoxicology. Wiley-Liss, New York, pp 159–171Google Scholar
  267. Houston JB, Galetin A (2008) Methods for predicting in vivo pharmacokinetics using data from in vitro assays. Curr Drug Metab 9(9):940–951PubMedGoogle Scholar
  268. Hu T, Gibson DP, Carr GJ, Torontali SM, Tiesman JP, Chaney JG, Aardema MJ (2004) Identification of a gene expression profile that discriminates indirect-acting genotoxins from direct-acting genotoxins. Mutat Res 549:5–27PubMedGoogle Scholar
  269. Hu T, Kaluzhny Y, Mun GC, Barnett B, Karetsky V, Wilt N, Klausner M, Curren R, Aardema MJ (2009) Intralaboratory and interlaboratory evaluation of the EpiDermTM 3D human reconstructed skin micronucleus (RSMN) assay. Mutat Res 673:100–108PubMedGoogle Scholar
  270. Hu T, Khambatta ZS, Hayden PJ, Bolmarcich J, Binder RL, Robinson MK, Carr GJ, Tiesman JP, Jarrold BB, Osborne R, Reichling TD, Nemeth ST, Aardema MJ (2010) Xenobiotic metabolism gene expression in the EpiDerm in vitro 3D human epidermis model compared to human skin. Toxicol In Vitro 24:1450–1463PubMedGoogle Scholar
  271. Huang S (2009) Standardization and pre-validation of MucilAir: a novel in vitro cell model of the human airway epithelium for testing acute and chronic effects of chemical compounds. 3R research foundation Switzerland 3R-project 106-07. Accessed 15 Jan 2011
  272. Hurtt ME, Cappon GD, Browning A (2003) Proposal for a tiered approach to developmental toxicity testing for veterinary pharmaceutical products for food-producing animals. Food Chem Toxicol 41:611–619PubMedGoogle Scholar
  273. Hwan Sung J, Esch MB, Shuler ML (2010) Integration of in silico and in vitro platforms for pharmacokinetic-pharmacodynamic modeling. Expert Opin Drug Metab Toxicol 6:1–19Google Scholar
  274. ILSI HESI ACT (2001) ILSI HESI alternatives to carcinogenicity testing project. Toxicol Pathol 29(supplement):1–351Google Scholar
  275. Isfort RJ, Kerckaert GA, LeBoeuf RA (1996) Comparison of the standard and reduced pH Syrian hamster embryo (SHE) cell in vitro transformation assays in predicting the carcinogenic potential of chemicals. Mutat Res 356:11–63PubMedGoogle Scholar
  276. Ishihara A, Rahman FB, Leelawatwattana L, Prapunpoj P, Yamauchi K (2009) In vitro thyroid hormone-disrupting activity in effluents and surface waters in Thailand. Environ Toxicol Chem 28:586–594PubMedGoogle Scholar
  277. Jäckh C, Blatz V, Guth K, Reisinger K, Fabian E, van Ravenzwaay B, Landsiedel R (2010) Enzyme activities for xenobiotic metabolism in human reconstructed skin models. ALTEX 27(suppl 2/10):60Google Scholar
  278. Jagger C, Tate M, Cahill PA, Hughes C, Knight AW, Billinton N, Walmsley RM (2009) Assessment of the genotoxicity of S9-generated metabolites using the GreenScreen HC GADD45a-GFP assay. Mutagenesis 24:35–50PubMedGoogle Scholar
  279. Jamei M, Dickinson GL, Rostami-Hodjegan A (2009) A framework for assessing interindividual variability in pharmacokinetics using virtual human populations and integrating general knowledge of physical chemistry, biology, anatomy, physiology and genetics: a tale of ‘bottom-up’ vs ‘top-down’ recognition of covariates. Drug Metab Pharmacokinet 24:53–75PubMedGoogle Scholar
  280. Jaworska J, Nikolova-Jeliazkova N (2007) How can structural similarity analysis help in category formation. SAR QSAR Environ Res 18:195–207PubMedGoogle Scholar
  281. JECFA (1996) A procedure for the safety evaluation of flavouring agents. WHO food additive series 35. Annex 5. World Health Organization, GenevaGoogle Scholar
  282. JECFA (1997) Safety evaluation of certain food additives and contaminants. Forty-ninth report of the joint FAO/WHO expert committee on food additives. WHO food additive series 40. World Health Organization, GenevaGoogle Scholar
  283. Jelinek R (1977) The chick embryotoxicity screening test (CHEST). In: Neubert D, Merker HJ, Kwasigroch TE (eds) Methods in pre-natal toxicology. Thieme, Stuttgart, pp 381–386Google Scholar
  284. Jelinek R, Marhan O (1994) Validation of the chick embryotoxicity screening test (CHEST). A comparative study. Funct Dev Morphol 4:317–323PubMedGoogle Scholar
  285. Jelinek R, Peterka M, Rychter Z (1985) Chick embryotoxicity screening test—130 substances tested. Indian J Exp Biol 23:588–595PubMedGoogle Scholar
  286. Jennings P (2010) The role of the Nrf2 pathway in nephrotoxicity. ALTEX 27(suppl 2/10):60–61Google Scholar
  287. Jennings P, Aydin S, Bennett J, McBride R, Weiland C, Tuite N, Gruber LN, Perco P, Gaora PO, Ellinger-Ziegelbauer H, Ahr HJ, Van Kooten C, Daha MR, Prieto P, Ryan MP, Pfaller W, McMorrow T (2009) Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro 23(3):486–499PubMedGoogle Scholar
  288. Jensen GE, Niemela JR, Wedebye EB, Nikolov NG (2008) QSAR models for reproductive toxicity and endocrine disruption in regulatory use—a preliminary investigation. SAR QSAR Environ Res 19:631–641PubMedGoogle Scholar
  289. Jiang Y, Gerhold DL, Holder DJ, Figueroa DJ, Bailey WJ, Guan P, Skopek TR, Sistare FR, Sina JF (2007) Diagnosis of drug-induced renal tubular toxicity using global gene expression profiles. J Transl Med 5:47PubMedGoogle Scholar
  290. Jones HM, Gardner IB, Watson KJ (2009) Modelling and PBPK simulation in drug discovery. AAPS J 11:155–166PubMedGoogle Scholar
  291. 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, Luijten M (2009) Finding transcriptomics biomarkers for in vivo identification of (non-)genotoxic carcinogens using wild-type and Xpa/p53 mutant mouse models. Carcinogenesis 30:1805–1812PubMedGoogle Scholar
  292. Jowsey IR, Basketter DA, Westmoreland C, Kimber I (2006) A future approach to measuring relative skin sensitising potency: a proposal. J Appl Toxicol 26:341–350PubMedGoogle Scholar
  293. Kane KL, Ashton FA, Schmitz JL, Folds JD (1996) Determination of natural killer cell function by flow cytometry. Clin Diagn Lab Immunol 3(3):295–300PubMedGoogle Scholar
  294. Kapitulnik J, Pelkonen O, Gundert-Remy U, Dahl SG, Boobis AR (2009) Effects of pharmaceuticals and other active chemicals at biological targets: mechanisms, interactions, and integration into PB-PK/PD models. Expert Opin Therap Targets 13:867–887Google Scholar
  295. Karlberg AT, Basketter D, Goossens A, Lepoittevin JP (1999) Regulatory classification of substances oxidized to skin sensitisers by exposure to the air. Contact Derm 40(4):183–188PubMedGoogle Scholar
  296. Kasting G, Farahmand S, Nitsche J, Kern P, Gerberick F (2010) Epidermal bioavailability of volatile compounds. Application to fragrance disposition and skin sensitization risk assessment. Perfumer Flavorist 35Google Scholar
  297. Kawakami T, Ishimura R, Nohara K, Takeda K, Tohyama C, Ohsako S (2006) Differential susceptibilities of Holtzman and Sprague–Dawley rats to fetal death and placental dysfunction induced by 2,3,7,8-teterachlorodibenzo-p-dioxin (TCDD) despite the identical primary structure of the aryl hydrocarbon receptor. Toxicol Appl Pharmacol 212:224–236PubMedGoogle Scholar
  298. Keller D, Krauledat M, Scheel J (2009) Feasibility study to support a threshold of sensitization concern concept in risk assessment based on human data. Arch Toxicol 83(12):1049–1060PubMedGoogle Scholar
  299. Kemper FH, Luepke NP (1986) Toxicity testing by the hens egg test (het). Food Chem Toxicol 24:647–648Google Scholar
  300. Kettenhofen R, Bohlen H (2008) Preclinical assessment of cardiac toxicity. Drug Discov Today 13(15–16):702–707PubMedGoogle Scholar
  301. Kienhuis AS, Wortelboer HM, Maas WJ, van Herwijnen M, Kleinjans JC, van Delft JH, Stierum RH (2007) A sandwich-cultured rat hepatocyte system with increased metabolic competence evaluated by gene expression profiling. Toxicol In Vitro 21(5):892–901PubMedGoogle Scholar
  302. Kier LD, Neft R, Tang L, Suizu R, Cook T, Onsurez K, Tiegler K, Sakai Y, Ortiz M, Nolan T, Sankar U, Li AP (2004) Applications of microarrays with toxicologically relevant genes (tox genes) for the evaluation of chemical toxicants in Sprague–Dawley rats in vivo and human hepatocytes in vitro. Mutat Res 549(1–2):101–113PubMedGoogle Scholar
  303. Kikkawa R, Yamamoto T, Fukushima T, Yamada H, Horii I (2005) Investigation of a hepatotoxicity screening system in primary cell cultures: “what biomarkers would need to be addressed to estimate toxicity in conventional and new approaches?”. J Toxicol Sci 30(1):61–72Google Scholar
  304. Kikkawa R, Fujikawa M, Yamamoto T, Hamada Y, Yamada H, Horii I (2006) In vivo hepatotoxicity study of rats in comparison with in vitro hepatotoxicity screening system. J Toxicol Sci 31(1):23–34PubMedGoogle Scholar
  305. Kim MS, Lee W, Kim YC, Park JK (2008) Microvalve-assisted patterning platform for measuring cellular dynamics based on 3D cell culture. Biotechnol Bioeng 101(5):1005–1013PubMedGoogle Scholar
  306. Kimber I, Basketter DA (1992) The murine local lymph node assay: a commentary on collaborative studies and new directions. Food Chem Toxicol 30(2):165–169PubMedGoogle Scholar
  307. Kimber I, Cumberbatch M, Dearman RJ, Bhushan M, Griffiths CE (2000) Cytokines and chemokines in the initiation and regulation of epidermal Langerhans cell mobilization. Br J Dermatol 142(3):401–412PubMedGoogle Scholar
  308. Kimber I, Dearman RJ, Betts CJ, Gerberick GF, Ryan CA, Kern PS, Patlewicz GY, Basketter DA (2006) The local lymph node assay and skin sensitisation: a cut-down screen to reduce animal requirements? Contact Derm 54(4):181–185PubMedGoogle Scholar
  309. 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 25:539–553PubMedGoogle Scholar
  310. Kirkland D, Speit G (2008) 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 654:114–132PubMedGoogle Scholar
  311. Kirkland D, Aardema M, Henderson L, Müller 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 584:1–256PubMedGoogle Scholar
  312. Kirkland D, Aardema M, Müller L, Makoto H (2006) Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens II. Further analysis of mammalian cell results, relative predictivity and tumour profiles. Mutat Res 608:29–42PubMedGoogle Scholar
  313. Kirkland D, Pfuhler S, Tweats D, Aardema M, Corvi R, Darroudi F, Elhajouji A, Glatt H, Hastwell P, Hayashi M, Kasper P, Kirchner S, Lynch A, Marzin D, Maurici D, Meunier J-R, Müller L, Nohynek G, Parry J, Parry E, Thybaud V, Tice R, van Benthem J, Vanparys P, White P (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 628:31–55Google Scholar
  314. Kirkland D, Kasper P, Müller 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 653:99–108PubMedGoogle Scholar
  315. Klaunig JE, Shi Y (2009) Assessment of gap junctional intercellular communication. Curr Protoc Toxicol, chapter 2, unit 2.17Google Scholar
  316. Klaunig JE, Kamendulis LM, Hocevar BA (2010) Oxidative stress and oxidative damage in carcinogenesis. Toxicol Pathol 38:96–109PubMedGoogle Scholar
  317. Klopman G, Rosenkranz H (1994) Approaches to SAR in carcinogenesis and mutagenesis. Prediction of carcinogenicity/mutagenicity using MULTI-CASE. Mutat Res 305:33–46PubMedGoogle Scholar
  318. Klotz DM, Ladlie BL, Vonier PM, McLachlan JA, Arnold SF (1997) o,p′-DDT and its metabolites inhibit progesterone-dependent responses in yeast and human cells. Mol Cell Endocrinol 129:63–71PubMedGoogle Scholar
  319. Knight A, Jonker MJ, Bruning J (2005) Which drugs cause cancer? BMJ USA 5:477–478Google Scholar
  320. Knight A, Bailey J, Balcombe J (2006) Animal carcinogenicity studies: implications for the REACH system. Altern Lab Anim 34(suppl 1):139–147PubMedGoogle Scholar
  321. Kotwani A (1998) Use of chick embryo in screening for teratogenicity. Indian J Physiol Pharmacol 42:189–204PubMedGoogle Scholar
  322. Kramer NI (2010) Measuring, modeling and increasing the free concentration of test chemicals in cell assays. PhD thesis, Utrecht UniversityGoogle Scholar
  323. Kramer NI, Hermens JLM, Schirmer K (2009) The influence of modes of action and physicochemical properties of chemicals on the correlation between in vitro and acute fish toxicity data. Toxicol In Vitro 23:1372–1379PubMedGoogle Scholar
  324. Kreiling R, Hollnagel HM, Hareng L, Eigler D, Lee MS, Griem P, Dreesen B, Kleber M, Albrecht A, Garcia C, Wendel A (2008) Comparison of the skin sensitizing potential of unsaturated compounds and assessed by the murine local lymph node assay (LLNA) and the guinea pig maximization test (GPMT). Food Chem Toxicol 46(6):1896–1904PubMedGoogle Scholar
  325. Krewski D, Acosta D Jr, Andersen M, Anderson H, Bailar JC III, Boekelheide K, Brent R, Charnley G, Cheung VG, Green S Jr, Kelsey KT, Kerkvliet NI, Li AA, McCray L, Meyer O, Patterson RD, Pennie W, Scala RA, Solomon GM, Stephens M, Yager J, Zeise L (2010) Toxicity testing in the 21st century: a vision and a strategy. J Toxicol Environ Health B Crit Rev 13:51–138PubMedGoogle Scholar
  326. Kroes R, Kozianowski G (2002) Threshold of toxicological concern (TTC) in food safety assessment. Toxicol Lett 127(1–3):43–46PubMedGoogle Scholar
  327. Kroes R, Renwick AG, Cheeseman M, Kleiner J, Mangelsdorf I, Piersma A, Schilter B, Schlatter J, van Schothorst F, Vos JG, Würtzen G (2004) Structure-based thresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet. Food Chem Toxicol 42:65–83PubMedGoogle Scholar
  328. Kroes R, Kleiner J, Renwick A (2005) The threshold of toxicological concern concept in risk assessment. Toxicol Sci 86(2):226–230PubMedGoogle Scholar
  329. Kroes R, Renwick AG, Feron V, Galli CL, Gibney M, Greim H, Guy RH, Lhuguenot JC, van de Sandt JJ (2007) Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients. Food Chem Toxicol 45:2533–2562PubMedGoogle Scholar
  330. Krüse J, Golden D, Wilkinson S, Williams F, Kezic S, Corish J (2007) Analysis, interpretation, and extrapolation of dermal permeation data using diffusion-based mathematical models. J Pharmacol Sci 96:682–703Google Scholar
  331. Kucera P, Burnand MB (1987) Routine teratogenicity test that uses chick embryos in vitro. Teratog Carcinog Mutagen 7:427–447PubMedGoogle Scholar
  332. Kulkarni SA, Zhu J, Blechinger S (2005) In silico techniques for the study and prediction of xenobiotic metabolism: a review. Xenobiotica 35(10–11):955–973PubMedGoogle Scholar
  333. La SG, Farini D, De FM (2010) Estrogenic in vitro assay on mouse embryonic Leydig cells. Int J Dev Biol 54:717–722Google Scholar
  334. Lambrechts N, Vanheel H, Hooyberghs J, De Boever P, Witters H, Van Den Heuvel R, Van Tendeloo V, Nelissen I, Schoeters G (2010) Gene markers in dendritic cells unravel pieces of the skin sensitisation puzzle. Toxicol Lett 196(2):95–103PubMedGoogle Scholar
  335. Lambrot R, Muczynski V, Lecureuil C, Angenard G, Coffigny H, Pairault C, Moison D, Frydman R, Habert R, Rouiller-Fabre V (2009) Phthalates impair germ cell development in the human fetal testis in vitro without change in testosterone production. Environ Health Perspect 117:32–37PubMedGoogle Scholar
  336. Landsiedel R, Fabian E, Gamer A, Kolle S, Ma-Hock L, Schulz M, Wiench K, Wohlleben W, van Ravenzwaay B (2010) The use of alternative methods for toxicity testing of nanomaterials. ALTEX 27 (suppl 2/10):78Google Scholar
  337. Langezaal I, Hoffmann S, Hartung T, Coecke S (2002) Evaluation and prevalidation of an immunotoxicity test based on human whole-blood cytokine release. Altern Lab Anim 30(6):581–595PubMedGoogle Scholar
  338. Lankveld DP, Van Loveren H, Baken KA, Vandebriel RJ (2010) In vitro testing for direct immunotoxicity: state-of-the-art, chapter 26. In: Dietert RR (ed) Immunotoxicity testing: methods and protocols methods in molecular biology. Humana Press Inc., Totowa, pp 401–423Google Scholar
  339. Lappin G, Garner RC (2005) The use of accelerator mass spectrometry to obtain early human ADME/PK data. Expert Opin Drug Metab Toxicol 1(1):23–31PubMedGoogle Scholar
  340. Lazzari G, Tessaro I, Crotti G, Galli C, Hoffmann S, Bremer S, Pellizzer C (2008) Development of an in vitro test battery for assessing chemical effects on bovine germ cells under the ReProTect umbrella. Toxicol Appl Pharmacol 233:360–370PubMedGoogle Scholar
  341. Le Fevre AC, Boitier E, Marchandeau JP, Sarasin A, Thybaud V (2007) Characterization of DNA reactive and non-DNA reactive anticancer drugs by gene expression profiling. Mutat Res 619:16–29PubMedGoogle Scholar
  342. Lee PJ, Hung PJ, Lee LP (2007) An artificial liver sinusoid with a microfluidic endothelial-like barrier for primary hepatocyte culture. Biotechnol Bioeng 97(5):1340–1346PubMedGoogle Scholar
  343. Legendre A, Froment P, Desmots S, Lecomte A, Habert R, Lemazurier E (2010) An engineered 3D blood-testis barrier model for the assessment of reproductive toxicity potential. Biomaterials 31:4492–4505PubMedGoogle Scholar
  344. Lemeire K, Van Merris V, Cortvrindt R (2007) The antibiotic streptomycin assessed in a battery of in vitro tests for reproductive toxicology. Toxicol In Vitro 21:1348–1353PubMedGoogle Scholar
  345. Lewis DF, Ito Y (2008) Human cytochromes P450 in the metabolism of drugs: new molecular models of enzyme-substrate interactions. Experts Opin Drug Metab Toxicol 4(9):1181–1186Google Scholar
  346. Li AP (2008) In vitro evaluation of metabolic drug-drug interactions: scientific concepts and practical considerations. In: Gad SC (ed) Preclinical development handbook: ADME and biopharmaceutical properties, chapter 24. Wiley, New York, pp 853–878Google Scholar
  347. Li Z, Chan C (2009) Systems biology for identifying liver toxicity pathways. BMC Proc 3(suppl 2):S2Google Scholar
  348. Li W, Lam M, Choy D, Birkeland A, Sullivan ME, Post JM (2006) Human primary renal cells as a model for toxicity assessment of chemo-therapeutic drugs. Toxicol In Vitro 20(5):669–676PubMedGoogle Scholar
  349. Li HH, Aubrecht J, Fornace AJ Jr (2007) Toxicogenomics: overview and potential applications for the study of non-covalent DNA interacting chemicals. Mutat Res 623:98–108PubMedGoogle Scholar
  350. Liao KH, Tan YM, Clewell HJ (2007) Development of a screening approach to interpret human biomonitoring data on volatile organic compounds: reverse dosimetry on biomonitoring data for trichloroethylene. Risk Anal 27:1223–1236PubMedGoogle Scholar
  351. Lima BS, van der Laan JW (2000) Mechanisms of nongenotoxic carcinogenesis and assessment of the human hazard. Regul Toxicol Pharmacol 32:135–143Google Scholar
  352. Lippman M, Bolan G, Huff K (1976) The effects of estrogens and antiestrogens on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res 36:4595–4601PubMedGoogle Scholar
  353. Lo PK, Sukumar S (2008) Epigenomics and breast cancer. Pharmacogenomics 9:1879–1902PubMedGoogle Scholar
  354. Loeb LA, Harris CC (2008) Advances in chemical carcinogenesis: a historical review and prospective. Cancer Res 68:6863–6872PubMedGoogle Scholar
  355. Loizou GD, Spendiff M, Barton HA, Bessems J, Bois FY, d’Yvoire MB, Buist H, Clewell HJ III, Gundert-Remy U, Goerlitz G, Meek B Schmitt W (2008) Development of good modelling practice for physiologically based pharmacokinetic models for use in risk assessment: the first steps. Regul Toxicol Pharmacol 50:400–411Google Scholar
  356. Long M, Laier P, Vinggaard AM, Andersen HR, Lynggaard J, Bonefeld-Jorgensen EC (2003) Effects of currently used pesticides in the AhR-CALUX assay: comparison between the human TV101L and the rat H4IIE cell line. Toxicology 194:77–93PubMedGoogle Scholar
  357. López-Lázaro M (2010) A new view of carcinogenesis and an alternative approach to cancer therapy. Mol Med 16:144–153PubMedGoogle Scholar
  358. Luciano AM, Franciosi F, Lodde V, Corbani D, Lazzari G, Crotti G, Galli C, Pellizzer C, Bremer S, Weimer M, Modina SC (2010) Transferability and inter-laboratory variability assessment of the in vitro bovine oocyte maturation (IVM) test within ReProTect. Reprod Toxicol 30(1):81–88PubMedGoogle Scholar
  359. Luijten M, van Beelen VA, Verhoef A, Renkens MF, van Herwijnen MH, Westerman A, van Schooten FJ, Pennings JL, Piersma AH (2010) Transcriptomics analysis of retinoic acid embryotoxicity in rat postimplantation whole embryo culture. Reprod Toxicol 30:333–340PubMedGoogle Scholar
  360. Lyons MA, Yang RSH, Mayeno AN, Reisfeld B (2008) Computational toxicology of chloroform: reverse dosimetry using bayesian inference, markov chain monte carlo simulation, and human biomonitoring data. Environmental and health Perspectives 116:1040–1046Google Scholar
  361. Ma B, Zhang G, Qin J, Lin B (2009) Characterization of drug metabolites and cytotoxicity assay simultaneously using an integrated microfluidic device. Lab Chip 9(2):232–238PubMedGoogle Scholar
  362. Madden JC (2010) In silico approaches for predicting ADME properties. In: Puzyn T, Leszczynski J, Cronin MTD (eds) Recent advances in QSAR studies—methods and applications. Springer, Dordrecht, pp 283–304Google Scholar
  363. Magnusson B, Kligman AM (1970) Allergic contact dermatitis in the guinea pig: identification of contact allergens. Charles C. Thomas, SpringfieldGoogle Scholar
  364. MAQC Consortium (2006) The microarray quality control (MAQC) project shows inter- and intraplatform reproducibility of gene expression measurements. Nat Biotechnol 24:1151–1161Google Scholar
  365. Marchant C, Fisk L, Note R, Patel M, Surez D (2009) An expert system approach to the assessment of hepatotoxic potential. Chem Biodivers 6(11):2107–2114PubMedGoogle Scholar
  366. Martin MT, Judson RS, Reif DM, Kavlock RJ, Dix DJ (2009) Profiling chemicals based on chronic toxicity results from the US EPA ToxRef Database. Environ Health Perspect 117:392–399PubMedGoogle Scholar
  367. Martin SF, Esser PR, Schmucker S, Dietz L, Naisbitt DJ, Park BK, Vocanson M, Nicolas JF, Keller M, Pichler WJ, Peiser M, Luch A, Wanner R, Maggi E, Cavani A, Rustemeyer T, Richter A, Thierse HJ, Sallusto F (2010) T cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays. Cell Mol Life Sci 67(24):4171–4184PubMedGoogle Scholar
  368. Martínez-Jiménez CP, Castell JV, Gómez-Lechón MJ, Jover R (2006) Transcriptional activation of CYP2C9, CYP1A1, and CYP1A2 by hepatocyte nuclear factor 4alpha requires coactivators peroxisomal proliferator activated receptor-gamma coactivator 1alpha and steroid receptor coactivator 1. Mol Pharmacol 70(5):1681–1692PubMedGoogle Scholar
  369. Marx J (2003) Building better mouse models for studying cancer. Science 299:1972–1975PubMedGoogle Scholar
  370. Marx-Stoelting P, Adriaens E, Ahr HJ, Bremer S, Garthoff B, Gelbke HP, Piersma A, Pellizzer C, Reuter U, Rogiers V, Schenk B, Schwengberg S, Seiler A, Spielmann H, Steemans M, Stedman DB, Vanparys P, Vericat JA, Verwei M, van der Water F, Weimer M, Schwarz M (2009) A review of the implementation of the embryonic stem cell test (EST). The report and recommendations of an ECVAM/ReProTect workshop. Altern Lab Anim 37:313–328PubMedGoogle Scholar
  371. Mathijs K, Brauers KJ, Jennen DGJ, Lizarraga D, Kleinjans JCS, van Delft JHM (2010) Gene expression profiling in primary mouse hepatocytes discriminates true from false-positive genotoxic compounds. Mutagenesis 25:561–568PubMedGoogle Scholar
  372. Matthews EJ, Spalding JW, Tennant RW (1993) Transformation of BALB/c-3T3 cells: V. Transformation responses of 168 chemicals compared with mutagenicity in salmonella and carcinogenicity in rodent bioassays. Environ Health Perspect 101(suppl 2):347–482Google Scholar
  373. Matthews EJ, Kruhlak NL, Benz RD, Contrera JF (2004a) Assessment of the health effects of chemicals in humans: I. QSAR estimation of the maximum recommended therapeutic dose (MRTD) and no effect level (NOEL) of organic chemicals based on clinical trial data. Curr Drug Discov Technol 1(1):61–76Google Scholar
  374. Matthews EJ, Kruhlak NL, Weaver JL, Benz RD, Contrera JF (2004b) Assessment of the health effects of chemicals in humans: II. Construction of an adverse effects database for QSAR modeling. Curr Drug Discov Technol 1(4):243–254Google Scholar
  375. Matthews EJ, Kruhlak NL, Benz RD, Contrera JF, Marchant CA, Yang C (2008) Combined use of MC4PC, MDL-QSAR, BioEpisteme, Leadscope PDM, and Derek for Windows Software to achieve high-performance, high-confidence, mode of action-based predictions of chemical carcinogenesis in rodents. Toxicol Mech Methods 18:189–206PubMedGoogle Scholar
  376. Maunz A, Helma C (2008) Prediction of chemical toxicity with local support vector regression and activity-specific kernels. SAR QSAR Environ Res 19(5–6):413–431PubMedGoogle Scholar
  377. Maurici D, Aardema M, Corvi R, Kleber M, Krul C, Laurent C, Loprieno N, Pasanen M, Pfuhler S, Phillips B, Sabbioni E, Sanner T, Vanparys P (2005) Genotoxicty and mutagenicity. Altern Lab Anim 33(suppl 1):117–130Google Scholar
  378. Maxwell G, Mackay C (2008) Application of a systems biology approach to skin allergy risk assessment. Altern Lab Anim 36(5):521–556PubMedGoogle Scholar
  379. Mazzatorta P, Tran L-A, Schilter B, Grigorov M (2007) Integration of structure activity relationship and artificial intelligence systems to improve in silico prediction of Ames test mutagenicity. J Chem Inf Model 47(1):34–38PubMedGoogle Scholar
  380. Mazzatorta P, Estevez MD, Coulet M, Schilter B (2008) Modeling oral rat chronic toxicity. J Chem Inf Model 48(10):1949–1954PubMedGoogle Scholar
  381. McFadden JP, Basketter DA (2000) Contact allergy, irritancy and danger. Contact Derm 42(3):123–127PubMedGoogle Scholar
  382. McKim JM, Keller DJ, Gorski JR (2010) A new in vitro method for identifying chemical sensitizers combining peptide binding with ARE/EpRE-mediated gene expression in human skin cells. Cutan Ocul Toxicol 29(3):171–192Google Scholar
  383. Meek ME (2004) Biologically motivated computational modeling: contribution to risk assessment. Toxicol Sci 82:1–2PubMedGoogle Scholar
  384. Mehdipour AR, Hamidi M (2009) Brain drug targeting: a computational approach for overcoming blood–brain barrier. Drug Discov Today 14:1030–1036PubMedGoogle Scholar
  385. Mekenyan O, Dimitrov S, Serafimova R, Thompson E, Kotov S, Dimitrova N, Walker JD (2004) Identification of the structural requirements for mutagenicity by incorporating molecular flexibility and metabolic activation of chemicals I: TA100 model. Chem Res Toxicol 17:753–766PubMedGoogle Scholar
  386. Mekenyan O, Todorov M, Serafimova R, Stoeva S, Aptula A, Finking R, Jacob E (2007) Identifying the structural requirements for chromosomal aberration by incorporating molecular flexibility and metabolic activation of chemicals. Chem Res Toxicol 20:1927–1941PubMedGoogle Scholar
  387. Mellman I, Steinman RM (2001) Dendritic cells: specialized and regulated antigen processing machines. Cell 106(3):255–258PubMedGoogle Scholar
  388. Meneses-Lorente G, Watt A, Salim K, Gaskell SJ, Muniappa N, Lawrence J, Guest PC (2006) Identification of early proteomic markers for hepatic steatosis. Chem Res Toxicol 19(8):986–998PubMedGoogle Scholar
  389. Mielke H, Anger LT, Schug M, Hengstler JG, Stahlmann R, Gundert-Remy U (2010) A physiologically based toxicokinetic modelling approach to predict relevant concentrations for in vitro testing. Arch Toxicol [Epub ahead of print]Google Scholar
  390. Miller CL, Eaves CJ (2002) Long-term culture-initiating cell assays for human and murine cells. In: Klug CA, Jordan CT (eds) Haematopoietic stem cell protocols. Humana Press Inc., New Jersey, pp 123–141Google Scholar
  391. Molina-Molina JM, Hillenweck A, Jouanin I, Zalko D, Cravedi JP, Fernandez MF, Pillon A, Nicolas JC, Olea N, Balaguer P (2006) Steroid receptor profiling of vinclozolin and its primary metabolites. Toxicol Appl Pharmacol 216:44–54PubMedGoogle Scholar
  392. Moore P, Ogilvie J, Horridge E, Mellor IR, Clothier RH (2005) The development of an innervated epithelial barrier model using a human corneal cell line and ND7/23 sensory neurons. Eur J Cell Biol 84(5):581–592PubMedGoogle Scholar
  393. Morck TJ, Sorda G, Bechi N, Rasmussen BS, Nielsen JB, Ietta F, Rytting E, Mathiesen L, Paulesu L, Knudsen LE (2010) Placental transport and in vitro effects of Bisphenol A. Reprod Toxicol 30(1):131–137PubMedGoogle Scholar
  394. Mortishire-Smith RJ, Skiles GL, Lawrence JW, Spence S, Nicholls AW, Johnson BA, Nicholson JK (2004) Use of metabonomics to identify impaired fatty acid metabolism as the mechanism of a drug-induced toxicity. Chem Res Toxicol 17(2):165–173PubMedGoogle Scholar
  395. Mose T, Kjaerstad MB, Mathiesen L, Nielsen JB, Edelfors S, Knudsen LE (2008) Placental passage of benzoic acid, caffeine, and glyphosate in an ex vivo human perfusion system. J Toxicol Environ Health A 71:984–991PubMedGoogle Scholar
  396. Moss E, Lynagh S, Smith D, Kelly S, McDaid A, Bunton D (2010) A novel system for the investigation of microvascular dysfunction including vascular permeability and flow-mediated dilatation in pressurised human arteries. J Pharmacol Toxicol Methods 62(1):40-46Google Scholar
  397. Mostrag-Szlichtyng A, Worth A (2010) Review of QSAR models and software tools for predicting biokinetic properties. EUR 24377 EN. European Commission, LuxembourgGoogle Scholar
  398. Müller L, Mauthe RJ, Riley CM, Andino MM, Antonis DD, Beels C, DeGeorge J, De Knaep AG, Ellison D, Fagerland JA, Frank R, Fritschel B, Galloway S, Harpur E, Humfrey CD, Jacks AS, Jagota N, Mackinnon J, Mohan G, Ness DK, O’Donovan MR, Smith MD, Vudathala G, Yotti L (2006) A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity. Regul Toxicol Pharmacol 44:198–211PubMedGoogle Scholar
  399. Mumtaz MM, Knauf LA, Reisman DJ, Peirano WB, DeRosa CT, Gombar VK, Enslein K, Carter JR, Blake BW, Huque KI, Ramanujam MS (1995) Assessment of effect levels of chemicals from quantitative structure–activity relationship (QSAR) models. I. Chronic lowest-observed-adverse effect level (LOAEL). Toxicol Lett 79(1–3):131–143Google Scholar
  400. Mun GC, Aardema MJ, Hu T, Barnett B, Kaluzhny Y, Klausner M, Karetsky V, Dahl EL, Curren RD (2009) Further development of the EpiDermTM 3D reconstructed human skin micronucleus (RSMN) assay. Mutat Res 673:92–99PubMedGoogle Scholar
  401. Munro IC, Ford RA, Kennepohl E, Sprenger JG (1996a) Thresholds of toxicological concern based on structure–activity relationships. Drug Metab Rev 28(1–2):209–217PubMedGoogle Scholar
  402. Munro IC, Ford RA, Kennepohl E, Sprenger JG (1996b) Correlation of structural class with no-observed effect levels: a proposal for establishing a threshold of concern. Food ChemToxicol 34:829–867Google Scholar
  403. Munro IC, Renwick AG, Danielewska-Nikiel B (2008) The threshold of toxicological concern (TTC) in risk assessment. Toxicol Lett 180(2):151–156PubMedGoogle Scholar
  404. Muster W, Breidenbach A, Fischer H, Kirchner S, Muller L, Pahler A (2008) Computational toxicology in drug development. Drug Discov Today 13(7–8):303–310PubMedGoogle Scholar
  405. Myllynen P, Immonen E, Kummu M, Vahakangas K (2009) Developmental expression of drug metabolizing enzymes and transporter proteins in human placenta and fetal tissues. Expert Opin Drug Metab Toxicol 5:1483–1499PubMedGoogle Scholar
  406. Myren M, Mose T, Mathisen L, Knudsen LE (2007) The human placenta—an alternative to foetal exposure. Toxicol In Vitro 21:1332–1340PubMedGoogle Scholar
  407. Nagel R (2002) DarT: the embryo test with the zebrafish danio rerio—a general model in ecotoxicology and toxicology. ALTEX 19(suppl 1):38–48Google Scholar
  408. Naiki T, Nagaki M, Asano T, Kimata T, Moriwaki H (2005) Adenovirus-mediated hepatocyte nuclear factor-4alpha overexpression maintains liver phenotype in cultured rat hepatocytes. Biochem Biophys Res Commun 335(2):496–500PubMedGoogle Scholar
  409. Nakai D, Kumamoto K, Sakikawa Ch, Kosaka T, Tokui T (2004) Evaluation of protein binding ratio of drugs by a micro-scale uktracentrifugation method. J Pharmaceut Sci 93:847–851Google Scholar
  410. Natsch A (2010) The Nrf2-Keap1-ARE toxicity pathway as a cellular sensor for skin sensitisers functional relevance and a hypothesis on innate reactions to skin sensitisers. Toxicol Sci 113(2):284–292PubMedGoogle Scholar
  411. Natsch A, Emter R (2008) Skin sensitisers induce antioxidant response element dependent genes: application to the in vitro testing of the sensitisation potential of chemicals. Toxicol Sci 102(1):110–119PubMedGoogle Scholar
  412. Natsch A, Gfeller H (2008) LC–MS based characterization of the peptide reactivity of chemicals to improve the in vitro prediction of the skin sensitisation potential. Toxicol Sci 106(2):464–478Google Scholar
  413. Natsch A, Emter R, Ellis G (2009) Filling the concept with data: integrating data from different in vitro and in silico assays on skin sensitisers to explore the battery approach for animal-free skin sensitisation testing. Toxicol Sci 107(1):106–121PubMedGoogle Scholar
  414. Nestorov I (2003) Whole body pharmacokinetic models. Clin Pharmacokinet 42:883–908PubMedGoogle Scholar
  415. Nestorov I (2007) Whole-body physiologically based pharmacokinetic models. Expert Opin Drug Metab Toxicol 3:235–249PubMedGoogle Scholar
  416. Nie AY, McMillian M, Parker JB, Leone A, Bryant S, Yieh L, Bittner A, Nelson J, Carmen A, Wan J, Lord PG (2006) Predictive toxicogenomics approaches reveal underlying molecular mechanisms of nongenotoxic carcinogenicity. Mol Carcinog 45:914–933PubMedGoogle Scholar
  417. Nioi P, Pardo ID, Sherratt PJ, Snyder RD (2008) Prediction of non-genotoxic carcinogenesis in rats using changes in gene expression following acute dosing. Chem Biol Interact 172:206–215PubMedGoogle Scholar
  418. Nohynek GJ, Antignac E, Re T, Toutain H (2010) Safety assessment of personal care products/cosmetics and their ingredients. Toxicol Appl Pharmacol 243(2):239–259PubMedGoogle Scholar
  419. NRC, National Research Council (2007) Toxicity testing in the 21st century: a vision and a strategy. National Academies Press, Washington, DCGoogle Scholar
  420. OECD, Organisation for Economic Cooperation and Development (1981a) Test guideline on repeated dose dermal toxicity: 21/28-day study, ParisGoogle Scholar
  421. OECD, Organisation for Economic Cooperation and Development (1981b) Test guideline on repeated dose dermal toxicity: 90-day study, ParisGoogle Scholar
  422. OECD, Organisation for Economic Cooperation and Development (1983) Guideline for the testing of chemicals 415. One-generation reproduction toxicity study, ParisGoogle Scholar
  423. OECD, Organisation for Economic Cooperation and Development (1992) Skin sensitisation guidelines for testing of chemicals no. 406, ParisGoogle Scholar
  424. OECD, Organisation for Economic Cooperation and Development (1995) Guideline for the testing of chemicals 421. Reproduction/developmental toxicity screening test, ParisGoogle Scholar
  425. OECD, Organisation for Economic Cooperation and Development (1996) Guideline for the testing of chemicals 422. Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, ParisGoogle Scholar
  426. OECD, Organisation for Economic Cooperation and Development (1998a) Test guideline on repeated Dose 90-day oral toxicity study in rodents, ParisGoogle Scholar
  427. OECD, Organisation for Economic Cooperation and Development (1998b) Test guideline on repeated dose 90-day oral toxicity study in non-rodents, ParisGoogle Scholar
  428. OECD, Organisation for Economic Cooperation and Development (2001a) Guideline for the testing of chemicals 414. Prenatal development toxicity study, ParisGoogle Scholar
  429. OECD, Organisation for Economic Cooperation and Development (2001b) Guideline for the testing of chemicals 416. Two-generation reproduction toxicity, ParisGoogle Scholar
  430. OECD, Organisation for Economic Cooperation and Development (2002) The local lymph node assay. Guidelines for testing of chemicals no. 429, ParisGoogle Scholar
  431. OECD, Organisation for Economic Cooperation and Development (2004a) OECD series on testing and assessment number 49. Report from the expert group on (quantitative) structure–activity relationships [(Q)SARs] on the principles for the validation of (Q)SARs, ParisGoogle Scholar
  432. OECD, Organisation for Economic Cooperation and Development (2004b) Test guideline 428. Skin absorption: in vitro method. Available via
  433. OECD, Organisation for Economic Cooperation and Development (2007a) Guidance document on the validation of (quantitative) structure–activity relationships [(Q)SAR] models, ParisGoogle Scholar
  434. OECD, Organisation for Economic Cooperation and Development (2007b) Guidance on grouping of chemicals, OECD environment health and safety publications, series on testing and assessment no. 80.
  435. OECD, Organisation for Economic Cooperation and Development (2007c) Guideline for the testing of chemicals 426. Developmental neurotoxicity study, ParisGoogle Scholar
  436. OECD, Organisation for Economic Cooperation and Development (2007d) Guideline for the testing of chemicals 440. Uterotrophic bioassay in rodents. A short-term screening test for oestrogenic properties, ParisGoogle Scholar
  437. OECD, Organisation for Economic Cooperation and Development (2007e) Detailed review on cell transformation assays for detection of chemical carcinogens, OECD environment, health and safety publications, series on testing and assessment, no. 31.
  438. OECD, Organisation for Economic Cooperation and Development (2008a) Test guideline on repeated Dose 28-day oral toxicity study in rodents, ParisGoogle Scholar
  439. OECD, Organisation for Economic Cooperation and Development (2008b) Guidance document 43: guidance document on mammalian reproductive toxicity testing and assessment, ParisGoogle Scholar
  440. OECD, Organisation for Economic Cooperation and Development (2009a) Test guideline on subacute inhalation toxicity: 28-day study, ParisGoogle Scholar
  441. OECD, Organisation for Economic Cooperation and Development (2009b). OECD guideline for the testing of chemicals 441. Hershberger bioassay in rats. A short-term screening assay for (anti)androgenic properties, ParisGoogle Scholar
  442. OECD, Organisation for Economic Cooperation and Development (2009c). OECD guideline for the testing of chemicals 455. The stably transfected human estrogen receptor-alpha transcriptional activation assay for detection of estrogenic agonist-activity of chemicals, ParisGoogle Scholar
  443. OECD, Organisation for Economic Cooperation and Development (2009d). OECD draft proposal for an extended one-generation reproductive toxicity study, ParisGoogle Scholar
  444. OECD, Organisation for Economic Cooperation and Development (2009e) Test guideline on subchronic inhalation toxicity: 90-day study, ParisGoogle Scholar
  445. OECD, Organisation for Economic Cooperation and Development (2009f) Test guideline on chronic toxicity studies, ParisGoogle Scholar
  446. OECD, Organisation for Economic Cooperation and Development (2010a) Guidelines for the testing of chemicals, section 4: health effects. Test no. 417: Toxicokinetics, ParisGoogle Scholar
  447. OECD, Organisation for Economic Cooperation and Development (2010b) Skin sensitization: local lymph node assay: DA, guidelines for testing of chemicals no. 442A, ParisGoogle Scholar
  448. OECD, Organisation for Economic Cooperation and Development (2010c) Skin sensitization: local lymph node assay: BrdU-ELISA, guidelines for testing of chemicals no. 442B, ParisGoogle Scholar
  449. OECD, Organisation for Economic Cooperation and Development (2010d) Accessed 30 June 2010
  450. OECD, Organisation for Economic Cooperation and Development (2010e) OECD guideline for the testing of chemicals draft proposal for a new guideline 4XX. The H295R steroidogenisis assay, ParisGoogle Scholar
  451. OECD, Organisation for Economic Co-operation and Development (2004c) Guidance document 28 for the conduct of skin absorption studies, Paris, March, 1–31Google Scholar
  452. Ohmori K, Umeda M, Tanaka N, Takagi H, Yoshimura I, Sasaki K, Asada S, Sakai A, Araki H, Asakura M, Baba H, Fushiwaki Y, Hamada S, Kitou N, Nakamura T, Nakamura Y, Oishi H, Sasaki S, Shimada S, Tsuchiya T, Uno Y, Washizuka M, Yajima S, Yamamoto Y, Yamamura E, Yatsushiro T (2005) Non-genotoxic carcinogen study group in the environmental mutagen society of Japan. An inter-laboratory collaborative study by the non-genotoxic carcinogen study group in Japan, on a cell transformation assay for tumour promoters using Bhas 42 cells. Altern Lab Anim 33:619–639Google Scholar
  453. Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J, Sipes G, Bracken W, Dorato M, Van Deun K, Sith P, Berger B, Heller A (2000) Concordance of the toxicity of pharmaceuticals in humans and animals. Regul Toxicol Pharmacol 32(1):56–67PubMedGoogle Scholar
  454. Oomen AG, Tolls J, Sips AJ, Groten JP (2003) In vitro intestinal lead uptake and transport in relation to speciation. Arch Environ Contam Toxicol 44(1):116–124PubMedGoogle Scholar
  455. Oosterhuis B (2010) Trends in microdosing and other exploratory human pharmacokinetic studies for early drug development. Bioanalysis 2(3):377–379PubMedGoogle Scholar
  456. Orman MA, Arai K, Yarmush ML, Androulakis IP, Berthiaume F, Ierapetritou MG (2010) Metabolic flux determination in perfused livers by mass balance analysis: effect of fasting. Biotechnol Bioeng 107(5):825–835PubMedGoogle Scholar
  457. Osman AM, van Dartel DA, Zwart E, Blokland M, Pennings JL, Piersma AH (2010) Proteome profiling of mouse embryonic stem cells to define markers for cell differentiation and embryotoxicity. Reprod Toxicol 30:322–332PubMedGoogle Scholar
  458. Ott H, Bergström MA, Heise R, Skazik C, Zwadlo-Klarwasser G, Merk HF, Baron JM, Karlberg AT (2009) Cutaneous metabolic activation of carvoxime, a self-activating, skin-sensitizing prohapten. Chem Res Toxicol 22(2):399–405PubMedGoogle Scholar
  459. Ouwehand K, Santegoets SJ, Bruynzeel DP, Scheper RJ, de Gruijl TD, Gibbs S (2008) CXCL12 is essential for migration of activated Langerhans cells from epidermis to dermis. Eur J Immunol 38(11):3050–3059PubMedGoogle Scholar
  460. Ouwehand K, Spiekstra SW, Reinders J, Scheper RJ, de Gruijl TD, Gibbs S (2010) Comparison of a novel CXCL12/CCL5 dependent migration assay with CXCL8 secretion and CD86 expression for distinguishing sensitisers from non-sensitisers using MUTZ-3 Langerhans cells. Toxicol In Vitro 24(2):578–585PubMedGoogle Scholar
  461. Pant K, Sly JE, Bruce SW, Leung C, San RH (2008) Syrian hamster embryo (SHE) cell transformation assay with conditioned media (without X-ray irradiated feeder layer) using 2,4-diaminotoluene, 2,6-diaminotoluene and chloral hydrate. Mutat Res 654:108–113PubMedGoogle Scholar
  462. Paquette JA, Kumpf SW, Streck RD, Thomson JJ, Chapin RE, Stedman DB (2008) Assessment of the embryonic stem cell test and application and use in the pharmaceutical industry. Birth Defects Res B Dev Reprod Toxicol 83:104–111PubMedGoogle Scholar
  463. Park KB, Dalton-Brown E, Hirst C, Williams DP (2006) Selection of new chemical entities with decreased potential for adverse drug reactions. Eur J Pharmacol 549:1–8PubMedGoogle Scholar
  464. Parry JM, Parry E, Phrakonkham P, Corvi R (2010) Analysis of published data for top concentration considerations in mammalian cell genotoxicity testing. Mutagenesis 25:531–538PubMedGoogle Scholar
  465. Patlewicz GY, Worth A (2008) Review of data sources, QSARs and integrated testing strategies for skin sensitisation. EUR 23225 ENGoogle Scholar
  466. Patlewicz G, Aptula AO, Uriarte E, Roberts DW, Kern PS, Gerberick GF, Kimber I, Dearman RJ, Ryan CA, Basketter DA (2007) An evaluation of selected global (Q)SARs/expert systems for the prediction of skin sensitisation potential. SAR QSAR Environ Res 18(5–6):515–541PubMedGoogle Scholar
  467. Patlewicz G, Jeliazkova N, Gallegos Saliner A, Worth AP (2008) Toxmatch—a new software tool to aid in the development and evaluation of chemically similar groups. SAR QSAR Environ Res 19:397–412PubMedGoogle Scholar
  468. Pauwels M, Rogiers V (2009)The safety evaluation of cosmetic ingredients at the EU level and the use of 3R-alternatives: an update. Poster presentation in the “7th world congress on alternatives & animal use in the life sciences”, Rome, Italy. ALTEX 26(special issue):193Google Scholar
  469. Pauwels M, Rogiers V (2010) Human health safety evaluation of cosmetics in the EU: a legally imposed challenge to science. Toxicol Appl Pharmacol 243:260–274PubMedGoogle Scholar
  470. Pauwels M, Dejaegher B, Vander Heyden Y, Rogiers V (2009) Critical analysis of the SCCNFP/SCCP safety assessment of cosmetic ingredients (2000–2006). Food Chem Toxicol 47(4):898–905PubMedGoogle Scholar
  471. Pedersen F, de Bruijn J, Munn S, van Leeuwen K (2003) Assessment of additional testing needs under REACH—effects of (Q)SARs, risk based testing and voluntary industry initiatives, 33 pp., JRC Report EUR 20863. Accessed 11 July 2010
  472. Peer Consultation on Health Canada Draft Weight of Evidence Framework for Genotoxic Carcinogenicity (2005)
  473. Pelkonen O, Turpeinen M (2007) In vitro-in vivo extrapolation of hepatic clearance: biological tools, scaling factors, model assumptions and correct concentrations. Xenobiotica 37:1066–1089PubMedGoogle Scholar
  474. Pelkonen O, Turpeinen M, Uusitalo J, Rautio A, Raunio H (2005) Prediction of drug metabolism and interactions on the basis of in vitro investigations. Basic Clin Pharmacol Toxicol 96(3):167–175PubMedGoogle Scholar
  475. Pelkonen O, Kapitulnik J, Gundert-Remy U, Boobis AR, Stockis A (2008a) Local kinetics and dynamics of xenobiotics. Crit Rev Toxicol 38:697–720PubMedGoogle Scholar
  476. Pelkonen O, Tolonen A, Turpeinen M, Uusitalo J (2008b) In vitro metabolism in preclinical drug development. In: Gad SC (ed) Preclinical development handbook: ADME and biopharmaceutical properties, chapter 21. Wiley, New York, pp 743–774Google Scholar
  477. Pelkonen O, Turpeinen M, Hakkola J, Honkakoski P, Hukkanen J, Raunio H (2008c) Inhibition and induction of human cytochrome P450 enzymes—current status. Arch Toxicol 82:667–715PubMedGoogle Scholar
  478. Pelkonen O, Tolonen A, Korjamo T, Turpeinen M, Raunio H (2009a) From known knowns to known unknowns: predicting in vivo drug metabolites. Bioanalysis 1:393–414PubMedGoogle Scholar
  479. Pelkonen O, Tolonen A, Rousu T, Tursas L, Turpeinen M, Hokkanen J, Uusitalo J, Bouvier d’Yvoire M, Coecke S (2009b) Comparison of metabolic stability and metabolite identification of 55 ECVAM/ICCVAM validation compounds between human and rat liver homogenates and microsomes—a preliminary analysis. ALTEX.26(3):214–22Google Scholar
  480. Pendlington RU, Minter HJ, Stupart L, MacKay C, Roper CS, Sanders DJ, Pease CK (2008) Development of a modified in vitro skin absorption method to study the epidermal/dermal disposition of a contact allergen in human skin. Cutan Ocul Toxicol 27(4):283–294PubMedGoogle Scholar
  481. Péry AR, Brochot C, Desmots S, Boize M, Sparfel L, Fardel O (2010) Predicting in vivo gene expression in macrophages after exposure to benzo(a)pyrene based on in vitro assays and toxicokinetic/toxicodynamic models. Toxicol Lett 201(1):8–14Google Scholar
  482. Pessina A, Albella B, Bayo M, Bueren J, Brantom P, Casati S, Croera C, Gagliardi G, Foti P, Parchment R, Parent-Massin D, Schoeters G, Sibiril Y, Van Den Heuvel R, Gribaldo L (2003) Application of the CFU-GM assay to predict acute drug-induced neutropenia: an international blind trial to validate a prediction model for the maximum tolerated dose (MTD) of myelosuppressive xenobiotics. Toxicol Sci 75(2):355–367PubMedGoogle Scholar
  483. Pessina A, Malerba I, Gribaldo L (2005) Hematotoxicity testing by cell clonogenic assay in drug development and preclinical trials. Curr Pharm Des 11(8):1055–1065PubMedGoogle Scholar
  484. Pessina A, Bonomi A, Cavicchini L, Albella B, Cerrato L, Parent-Massin D, Sibiril Y, Parchment R, Behrsing H, Verderio P, Pizzamiglio S, Giangreco M, Baglio C, Coccè V, Sisto F, Gribaldo L (2010) Prevalidation of the rat CFU-GM assay for in vitro toxicology applications. Altern Lab Anim 38(2):105–117PubMedGoogle Scholar
  485. Peters AK, Wouwer GV, Weyn B, Verheyen GR, Vanparys P, Gompel JV (2008) Automated analysis of contractility in the embryonic stem cell test, a novel approach to assess embryotoxicity. Toxicol In Vitro 22:1948–1956PubMedGoogle Scholar
  486. Petrak J, Myslivcova D, Man P, Cmejla R, Cmejlova J, Vyoral D (2006) Proteomic analysis of iron overload in human hepatoma cells. Am J Physiol Gastrointest Liver Physiol 290(5):G1059–G1066PubMedGoogle Scholar
  487. Pfaller W, Balls M, Clothier R, Coecke S, Dierickx P, Ekwall B, Hanley BA, Hartung T, Prieto P, Ryan MP, Schmuck G, Sladowski D, Vericat JA, Wendel A, Wolf A, Zimmer J (2001) Novel advanced in vitro methods for long-term toxicity testing: the report and recommendations of ECVAM workshop 45. European centre for the validation of alternative methods. Altern Lab Anim 29(4):393–426Google Scholar
  488. Pfuhler S, Kirkland D, Kasper P, Hayashi M, Vanparys P, Carmichael P, Dertinger S, Eastmond D, Elhajouji A, Krul C, Rothfuss A, Schoening G, Smith A, Speit G, Thomas C, van Benthem J, Corvi R (2009). Reduction of use of animals in regulatory genotoxicity testing: identification and implementation opportunities—report from an ECVAM workshop. Mutat Res 680:31–42Google Scholar
  489. Pfuhler S, Kirst A, Aardema M, Banduhn N, Goebel C, Araki D, Costabel-Farkas M, Dufour E, Fautz R, Harvey J, Hewitt NJ, Hibatallah J, Carmichael P, Macfarlane M, Reisinger K, Rowland J, Schellauf F, Schepky A, Scheel J (2010) A tiered approach to the use of alternatives to animal testing for the safety assessment of cosmetics: genotoxicity. A COLIPA analysis. Regul Toxicol Pharmacol 57:315–324PubMedGoogle Scholar
  490. Piersma AH (2006) Alternative methods for developmental toxicity testing. Basic Clin Pharmacol Toxicol 98:427–431PubMedGoogle Scholar
  491. Podestà M, Piaggio G, Pitto A, Zocchi E, Soracco M, Frassoni F, Luchetti S, Painelli E, Bacigalupo A (2001) Modified in vitro conditions for cord blood-derived long-term culture initiating cells. Exp Hematol 29(3):309–314PubMedGoogle Scholar
  492. Poth A, Kunz S, Heppenheimer A (2007) Bhas cell transformation assay as a predictor of carcinogenicity. ALTEX 14(special issue):519–521Google Scholar
  493. Poulin P, Theil FP (2002) Prediction of pharmacokinetics prior to in vivo studies. 1. Mechanism-based prediction of volume of distribution. J Pharmaceut Sci 91:129–156Google Scholar
  494. Poulin P, Theil FP (2009) Development of a novel method for predicting human volume distribution at steady-state of basic drugs and comparative assessment with existing methods. J Pharmaceut Sci 98:4941–4961Google Scholar
  495. Prieto P (2002) Barriers, nephrotoxicology and chronic testing in vitro. Altern Lab Anim 30(suppl 2):101–105Google Scholar
  496. Prieto P, Baird AW, Blaauboer BJ, Ripoll JV, Corvi R, Dekant W, Dietl P, Gennari A, Gribaldo L, Griffin JL, Hartung T, Heindel JJ, Hoet P, Jennings P, Marocchio L, Noraberg J, Pazos P, Westmoreland C, Wolf A, Wright J, Pfaller W (2006) The assessment of repeated dose toxicity in vitro: a proposed approach. The report and recommendations of ECVAM workshop 56. Altern Lab Anim 34(3):315–341Google Scholar
  497. Prieto P, Hoffmann S, Tirelli V, Tancredi F, Gonzàlez I, Bermejo M, De Angelis I (2010) An exploratory study of two caco-2 cell models for oral absorption: a report on their within-laboratory and between-laboratory variability, and their predictive capacity. ATLA 38(5):367–386Google Scholar
  498. Pritchard JB, French JE, Davis BJ, Haseman JK (2003) The role of transgenic mouse models in carcinogen identification. Environ Health Perspect 111:444–454PubMedGoogle Scholar
  499. Purdy R (1996) A mechanism-mediated model for carcinogenicity: model content and prediction of the outcome of rodent carcinogenicity bioassays currently being conducted on 25 organic chemicals. Environ Health Perspect 104:1085–1094PubMedGoogle Scholar
  500. Python F, Goebel C, Aeby P (2007) Assessment of the U937 cell line for the detection of contact allergens. Toxicol Appl Pharmacol 220(2):113–124PubMedGoogle Scholar
  501. Redfern WS, Ewart L, Hammond TG, Bialecki R, Kinter L, Lindgren S, Pollard CE, Roberts R, Rolf MG, Valentin JP (2010) Impact and frequency of different toxicities throughout the pharmaceutical life cycle (abstract 1081). Toxicologist 114:231Google Scholar
  502. Renwick AG (2004) Toxicology databases and the concept of thresholds of toxicological concern as used by the JECFA for the safety evaluation of flavouring agents. Toxicol Lett 149:223–234PubMedGoogle Scholar
  503. Ridings JE, Barratt MD, Cary R, Earnshaw CG, Eggington CE, Ellis MK, Judson PN, Langowski JJ, Marchant CA, Payne MP, Watson WP, Yih TD (1996) Computer prediction of possible toxic action from chemical structure: an update on the DEREK system. Toxicology 106:267–279PubMedGoogle Scholar
  504. Rietschel RL, Fowler JF (2008) Pathogenesis of allergic contact hypersensitivity. In: Fisher’s contact dermatitis, 6th edn. BC Decker Inc., Hamilton, pp 1–10Google Scholar
  505. Riley RJ, Kenna JG (2004) Cellular models for ADMET predictions and evaluation of drug-drug interactions. Curr Opin Drug Discov Dev 7(1):86–99Google Scholar
  506. Ringerike T, Ullerås E, Völker R, Verlaan B, Eikeset A, Trzaska D, Adamczewska V, Olszewski M, Walczak-Drzewiecka A, Arkusz J, van Loveren H, Nilsson G, Lovik M, Dastych J, Vandebriel RJ (2005) Detection of immunotoxicity using T-cell based cytokine reporter cell lines (‘cell chip’). Toxicology 206(2):257–272PubMedGoogle Scholar
  507. Rivedal E, Sanner T (1982) Promotional effect of different phorbol esters on morphological transformation of hamster embryo cells. Cancer Lett 17:1–8Google Scholar
  508. Roberts DW, Aptula AO (2008) Determinants of skin sensitisation potential. J Appl Toxicol 28(3):377–387PubMedGoogle Scholar
  509. Roberts DW, Patlewicz GY (2008) Nonanimal alternatives for skin sensitization: letter to the editor. Toxicol Sci 106(2):572–574PubMedGoogle Scholar
  510. Roberts DW, Patlewicz GY (2010) Updating the skin sensitization in vitro data assessment paradigm in 2009—a chemistry and QSAR perspective. J Appl Toxicol 30(3):286–288PubMedGoogle Scholar
  511. Roberts DW, Williams DL (1982) The derivation of quantitative correlations between skin sensitisation and physio-chemical parameters for alkylating agents, and their application to experimental data for sultones. J Theor Biol 99(4):807–825PubMedGoogle Scholar
  512. Roberts DW, Aptula AO, Patlewicz G (2007) Electrophilic chemistry related to skin sensitisation. Reaction mechanistic applicability domain classification for a published data set of 106 chemicals tested in the mouse local lymph node assay. Chem Res Toxicol 20(1):44–60Google Scholar
  513. Roberts DW, Schultz T, Wolf E, Aptula AO (2010) Experimental reactivity parameters for toxicity modeling: application to the acute aquatic toxicity of SN2 electrophiles to Tetrahymena pyriformis. Chem Res Tox 23(1):228–234Google Scholar
  514. Robinson JF, van Beelen VA, Verhoef A, Renkens MF, Luijten M, van Herwijnen MH, Westerman A, Pennings JL, Piersma AH (2010) Embryotoxicant-specific transcriptomic responses in rat postimplantation whole-embryo culture. Toxicol Sci 118:675–685PubMedGoogle Scholar
  515. Rohrbeck A, Salinas G, Maaser K, Linge J, Salovaara S, Corvi R, Borlak J (2010) Toxicogenomics applied to in vitro carcinogenicity testing with Balb/c 3T3 cells revealed a gene signature predictive of chemical carcinogens. Toxicol Sci 118:31–41PubMedGoogle Scholar
  516. Rostami-Hodjegan A, Tucker GT (2007) Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nat Rev Drug Discov 6:140–148PubMedGoogle Scholar
  517. Rotroff DM, Wetmore BA, Dix DJ, Ferguson SS, Clewell HJ, Houck KA, LeCluyse LE, Andersen ME, Judson RS, Smith CM, Sochaski MA, Kavlock RJ, Boellmann F, Martin MT, Reif DM, Wambaugh JF, Thomas RS (2010) Incorporating human dosimetry and exposure into high-throughput in vitro toxicity screening. Toxicol Sci 117:348–358PubMedGoogle Scholar
  518. Rougier N, Redziniak G, Mougin D, Schmitt D, Vincent C (2000) In vitro evaluation of the sensitisation potential of weak contact allergens using Langerhans-like dendritic cells and autologous T cells. Toxicology 145(1):73–82PubMedGoogle Scholar
  519. Rowland M, Balant L, Peck C (2004) Physiologically based pharmacokinetics in drug development and regulatory science: a workshop report (Georgetown University, Washington, DC, May 29–30, 2002). AAPS Pharm Sci 6:E6Google Scholar
  520. Roy A, Georgopoulos PG (1998) Reconstructing week-long exposures to volatile organic compounds using physiologically based pharmacokinetic models. J Expo Anal Environ Epidemiol 8:407–422PubMedGoogle Scholar
  521. Sadikovic B, Al-Romaih K, Squire JA, Zielenska M (2008) Cause and consequences of genetic and epigenetic alterations in human cancer. Curr Genom 9:394–408Google Scholar
  522. Safford RJ (2008) The dermal sensitisation threshold—a TTC approach for allergic contact dermatitis. Regul Toxicol Pharmacol 51(2):195–200PubMedGoogle Scholar
  523. Sakaguchi H, Ashikaga T, Miyazawa M, Yoshida Y, Ito Y, Yoneyama K, Hirota M, Itagaki H, Toyoda H, Suzuki H (2006) Development of an in vitro skin sensitisation test using human cell lines; human cell line activation test (h-CLAT). II. An inter laboratory study of the h-CLAT. Toxicol In Vitro 20(5):774–784Google Scholar
  524. Sakaguchi H, Ashikaga T, Miyazawa M, Kosaka N, Ito Y, Yoneyama K, Sono S, Itagaki H, Toyoda H, Suzuki H (2009) The relationship between CD86/CD54 expression and THP-1 cell viability in an in vitro skin sensitisation test—human cell line activation test (h-CLAT). Cell Biol Toxicol 2592:109–126Google Scholar
  525. Sanderson DM, Earnshaw CG (1991) Computer prediction of possible toxic action from chemical structure; the DEREK system. Hum Exp Toxicol 10:261–273PubMedGoogle Scholar
  526. Sanner T, Dybing E (2005) Comparison of carcinogenic and in vivo genotoxic potency estimates. Basic ClinPharmacol Toxicol 96:131–139Google Scholar
  527. Sawada H, Takami K, Asahi S (2005) A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci 83(2):282–292PubMedGoogle Scholar
  528. SCCNFP, European Commission’s Scientific Committee on Cosmetics and Non-Food Products (2000) Opinion concerning the predictive testing of potentially cutaneous sensitising cosmetic ingredients or mixtures of ingredients, 17 February 2000Google Scholar
  529. SCCNFP, European Commission’s Scientific Committee on Cosmetics and Non-Food Products (2003) Basic criteria for the in vitro assessment of dermal absorption of cosmetic ingredients, SCCNFP/0750/03. SCCNFP, BrusselsGoogle Scholar
  530. SCCP, European Commission’s Scientific Committee on Consumer’s Products (2008) Opinion on dermal sensitisation quantitative risk assessment (citral. farnesol and phenylacetaldehyde), 24 June 2008Google Scholar
  531. SCCP, Scientific Committee on Consumer Products (2006) The SCCP’s note of guidance for the testing of cosmetic ingredients and their safety evaluation, 6th revision, 106Google Scholar
  532. SCCS, European Commission’s Scientific Committee on Consumer Safety (2009) Memorandum on alternative test methods in human safety assessment of cosmetic ingredients in the European Union, 8 December 2009Google Scholar
  533. Schaafsma G, Kroese ED, Tielemans EL, Van de Sandt JJ, Van Leeuwen CJ (2009) REACH, non-testing approaches and the urgent need for a change in mind set. Regul Toxicol Pharmacol 53(1):70–80PubMedGoogle Scholar
  534. Schaefer WR, Fischer L, Deppert WR, Hanjalic-Beck A, Seebacher L, Weimer M, Zahradnik HP (2010) In vitro-Ishikawa cell test for assessing tissue-specific chemical effects on human endometrium. Reprod Toxicol 30(1):89–93PubMedGoogle Scholar
  535. Schenk B, Weimer M, Bremer S, van der Burg B, Cortvrindt R, Freyberger A, Lazzari G, Pellizzer C, Piersma A, Schafer WR, Seiler A, Witters H, Schwarz M (2010) The ReProTect feasibility study, a novel comprehensive in vitro approach to detect reproductive toxicants. Reprod Toxicol 30:200–218PubMedGoogle Scholar
  536. Schmelzer E, Mutig K, Schrade P, Bachmann S, Gerlach JC, Zeilinger K (2009) Effect of human patient plasma ex vivo treatment on gene expression and progenitor cell activation of primary human liver cells in multi-compartment 3D perfusion bioreactors for extra-corporeal liver support. Biotechnol Bioeng 103(4):817–827PubMedGoogle Scholar
  537. Schmidt CW (2009) TOX 21: new dimensions of toxicity testing. Environ Health Perspect 117(8):A348–A353PubMedGoogle Scholar
  538. Schmitt W (2008) General approach for the calculation of tissue to plasma partition coefficients. Toxicol In Vitro 22:457–467PubMedGoogle Scholar
  539. Schneider K, Akkan Z (2004) Quantitative relationship between the local lymph node assay and human skin sensitisation assays. Regul Toxicol Pharmacol 39(3):245–255PubMedGoogle Scholar
  540. Schreiner M, Peiser M, Briechle D, Stahlmann R, Zuberbier T, Wanner R (2007) A loose-fit coculture of activated keratinocytes and dendritic cell-related cells for prediction of sensitising potential. Allergy 62(12):1419–1428PubMedGoogle Scholar
  541. Schroder HJ (1995) Comparative aspects of placental exchange functions. Eur J Obstet Gynecol Reprod Biol 63:81–90PubMedGoogle Scholar
  542. Schultz TW, Yarbrough JW, Johnson EL (2005) Structures-activity relationships for reactivity of carbonyl-containing compounds with glutathione. SAR QSAR Environ Res 16(4):313–322PubMedGoogle Scholar
  543. Schultz TW, Rogers K, Aptula A (2009) Read-across to rank skin sensitisation potential: subcategories for the Michael acceptor domain. Contact Derm 60(1):21–31PubMedGoogle Scholar
  544. Selderslaghs IW, Van Rompay AR, De CW, Witters HE (2009) Development of a screening assay to identify teratogenic and embryotoxic chemicals using the zebrafish embryo. Reprod Toxicol 28:308–320PubMedGoogle Scholar
  545. Sens-it-iv (2010) Novel testing strategies for in vitro assessment of allergens. Available at Accessed 14 July 2010
  546. Serafimova R, Todorov M, Pavlov T, Kotov S, Jacob E, Aptula A, Mekenyan O (2007) Identification of the structural requirements for mutagenicity, by incorporating molecular flexibility and metabolic activation of chemicals. II. General Ames mutagenicity model. Chem Res Toxicol 20:662–676PubMedGoogle Scholar
  547. Serafimova R, Fuart Gatnik M, Worth A (2010) Review of QSAR models and software tools for predicting genotoxicity and carcinogenicity. EUR 24427 EN.
  548. Shanks N, Greek R, Greek J (2009) Are animal models predictive for humans? Philos Ethics Humanit Med 4:1–20Google Scholar
  549. Shen O, Du G, Sun H, Wu W, Jiang Y, Song L, Wang X (2009) Comparison of in vitro hormone activities of selected phthalates using reporter gene assays. Toxicol Lett 191:9–14PubMedGoogle Scholar
  550. Smialowicz RJ (1995) Immune function testing for the identification and characterisation of immunotoxicity in rodents. Hum Exp Toxicol 14(1):135–136PubMedGoogle Scholar
  551. Smith CK, Hotchkiss SA (2001) Allergic contact dermatitis. Taylor & Francis, London, pp 1–16Google Scholar
  552. Smithing MP, Darvas F (1992) Hazardexpert: an expert system for predicting chemical toxicity. In: Finlay JW, Robinson SF, Armstrong DJ (eds) Food safety assessment. American Chem Society, Washington, DC, pp 191–200Google Scholar
  553. Snykers S, Vanhaecke T, Papeleu P, Luttun A, Jiang Y, Vander Heyden Y, Verfaillie C, Rogiers V (2006) Sequential exposure to cytokines reflecting embryogenesis: the key for in vitro differentiation of adult bone marrow stem cells into functional hepatocyte-like cells. Toxicol Sci 94:330–341PubMedGoogle Scholar
  554. Snykers S, De Kock J, Vanhaecke T, Rogiers V (2007) Differentiation of neonatal rat epithelial cells from biliary origin into immature hepatic cells by sequential exposure to hepatogenic cytokines and growth factors reflecting liver development. Toxicol In Vitro 21(7):1325–1331PubMedGoogle Scholar
  555. Snykers S, De Kock J, Rogiers V, Vanhaecke T (2009) In vitro differentiation of embryonic and adult stem cells into hepatocytes: state of the art. Stem Cells 27:577–605PubMedGoogle Scholar
  556. Sohn MD, McKone TE, Blancato JN (2004) Reconstructing population exposures from dose biomarkers: inhalation of trichloroethylene (TCE) as a case study. J Expo Anal Environ Epidemiol 14:204–213PubMedGoogle Scholar
  557. Spanhaak S, Cook D, Barnes J, Reynolds J (2008) Species concordance for liver injury: from the safety intelligence program board. BioWisdom, Ltd, Cambridge. Available at Accessed 15 Jan 2011
  558. Speit G (2009) How to assess the mutagenic potential of cosmetic products without animal tests? Mutat Res 678:108–112PubMedGoogle Scholar
  559. Spiekstra SW, dos Santos GG, Scheper RJ, Gibbs S (2009) Potential method to determine irritant potency in vitro—comparison of two reconstructed epidermal culture models with different barrier competency. Toxicol In Vitro 23(2):349–355PubMedGoogle Scholar
  560. Sreejit P, Kumar S, Verma RS (2008) An improved protocol for primary culture of cardiomyocyte from neonatal mice. In Vitro Cell Dev Biol Anim 44(3–4):45–50PubMedGoogle Scholar
  561. Steiner G, Suter L, Boess F, Gasser R, de Vera MC, Albertini S, Ruepp S (2004) Discriminating different classes of toxicants by transcript profiling. Environ Health Perspect 112(12):1236–1248PubMedGoogle Scholar
  562. Stemmer K, Ellinger Ziegelbauer H, Ahr HJ, Dietrich DR (2007) Carcinogen-specific gene expression profiles in short-term treated Eker and wild-type rats indicative of pathways involved in renal tumorigenesis. Cancer Res 67:4052–4068PubMedGoogle Scholar
  563. Stummann TC, Bremer S (2008) The possible impact of human embryonic stem cells on safety pharmacological and toxicological assessments in drug discovery and drug development. Curr Stem Cell Res Ther 3:118–131PubMedGoogle Scholar
  564. Stummann TC, Beilmann M, Duker G, Dumotier B, Fredriksson JM, Jones RL, Hasiwa M, Kang YJ, Mandenius CF, Meyer T, Minotti G, Valentin YJ, Zünkler BJ, Bremer S (2009a) Report and recommendations of the workshop of the European centre for the validation of alternative methods for drug-induced cardiotoxicity. Cardiovasc Toxicol 9(3):107–125PubMedGoogle Scholar
  565. Stummann TC, Hareng L, Bremer S (2009b) Hazard assessment of methylmercury toxicity to neuronal induction in embryogenesis using human embryonic stem cells. Toxicology 257:117–126PubMedGoogle Scholar
  566. Sutherland HJ, Lansdorp PM, Henkelman DH, Eaves AC, Eaves CJ (1990) Functional characterization of individual human hematopoietic stem cells cultured at limiting dilution on supportive marrow stromal layers. Proc Natl Acad Sci USA 87(9):3584–3588PubMedGoogle Scholar
  567. Suuronen EJ, Nakamura M, Watsky MA, Stys PK, Muller LJ, Munger R, Shinozaki N, Griffith M (2004) Innervated human corneal equivalents as in vitro models for nerve-target cell interactions. FASEB J 18(1):170–172PubMedGoogle Scholar
  568. Suzuki M, Morihiko H, Hagino S, Itagaki H, Aiba S (2009) Evaluation of changes of cell-surface thiols as a new biomarker for in vitro sensitisation test. Toxicol In Vitro 23(4):687–696PubMedGoogle Scholar
  569. Taléns-Visconti R, Bonora A, Jover R, Mirabet V, Carbonell F, Castell JV, Gómez-Lechón MJ (2006) Hepatogenic differentiation of human mesenchymal stem cells from adipose tissue in comparison with bone marrow mesenchymal stem cells. World J Gastroenterol 12(36):5834–5845PubMedGoogle Scholar
  570. Tan YM, Liao KH, Clewell HJ (2006a) Reverse dosimetry: interpreting trihalomethanes biomonitoring data using physiologically based pharmacokinetic modeling. J Expo Anal Environ Epidemiol 17:591–603Google Scholar
  571. Tan YM, Liao KH, Conolly RB, Blount BC, Mason AM, Clewell HJ (2006b) Use of a physiologically based pharmacokinetic model to identify exposures consistent with human biomonitoring data for chloroform. J Toxicol Environ Health A 69:1727–1756PubMedGoogle Scholar
  572. Tang W, Lu AYH (2010) Metabolic bioactivation and drug-related adverse effects: current status and future directions from a pharmaceutical research perspective. Drug Metab Rev 42:225–249PubMedGoogle Scholar
  573. Tatosian DA, Shuler ML (2009) A novel system for evaluation of drug mixtures for potential efficacy in treating multidrug resistant cancers. Biotechnol Bioeng 103:187–198PubMedGoogle Scholar
  574. 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 103:942–950PubMedGoogle Scholar
  575. Tennant RW, Stasiewicz S, Mennear J, French JE, Spalding JW (1999) Genetically altered mouse models for identifying carcinogens. IARC Sci Publ 146:123–150PubMedGoogle Scholar
  576. Testa B, Balmat AL, Long A (2004) Predicting drug metabolism: concepts and challenges. Pure Appl Chem 76(5):907–914Google Scholar
  577. Theunissen PT, Schulpen SH, van Dartel DA, Hermsen SA, van Schooten FJ, Piersma AH (2010) An abbreviated protocol for multilineage neural differentiation of murine embryonic stem cells and its perturbation by methyl mercury. Reprod Toxicol 29:383–392PubMedGoogle Scholar
  578. Thierbach R, Steinberg P (2009) Automated soft agar assay for the high-throughput screening of anticancer compounds. Anal Biochem 387:318–320PubMedGoogle Scholar
  579. Tilaoui L, Schilter B, Tran LA, Mazzatorta P, Grigorov M (2007) Integrated computational methods for prediction of the lowest observable adverse effect level of food-borne molecules. QSAR Comb Sci 26(1):102–108Google Scholar
  580. Tolonen A, Turpeinen M, Pelkonen O (2009) Liquid chromatography-mass spectrometry in in vitro drug metabolite screening. Drug Discov Today (DDT) 14:120–133Google Scholar
  581. Toropov AA, Toropova AP, Benfenati E (2009) Additive SMILES-based carcinogenicity models: probabilistic principles in the search for robust predictions. Int J Mol Sci 10:3106–3127PubMedGoogle Scholar
  582. Tsujimura K, Asamoto M, Suzuki S, Hokaiwado N, Ogawa K, Shirai T (2006) Prediction of carcinogenic potential by a toxicogenomic approach using rat hepatoma cells. Cancer Sci 97:1002–1010PubMedGoogle Scholar
  583. Turpeinen M, Ghiciuc C, Orpitoui M, Kankainen L, Pelkonen O, Pasanen M (2007) Predictive value of animal models for human cytochrome P450 (CYP)-mediated enzymes: a comparative study in vitro. Xenobiotica 37:1367–1377PubMedGoogle Scholar
  584. Uchino T, Taketzava T, Ikarashi Y (2009) Reconstruction of three-dimensional human skin model composed of dendritic cells, keratinocytes and fibroblasts utilizing a handy scaffold of collagen vitrigel membrane. Toxicol In Vitro 23(2):333–337PubMedGoogle Scholar
  585. Uehara T, Hirode M, Ono A, Kiyosawa N, Omura K, Shimizu T, Mizukawa Y, Miyagishima T, Nagao T, Urushidani T (2008) A toxicogenomics approach for early assessment of potential non-genotoxic hepatocarcinogenicity of chemicals in rats. Toxicology 250:15–26PubMedGoogle Scholar
  586. Uibel F, Muhleisen A, Kohle C, Weimer M, Stummann TC, Bremer S, Schwarz M (2009) ReProGlo: a new stem cell-based reporter assay aimed to predict embryotoxic potential of drugs and chemicals. Reprod Toxicol 30(1):103–112PubMedGoogle Scholar
  587. Urani C, Stefanini FM, Bussinelli L, Melchioretto P, Crosta GF (2009) Image analysis and automatic classification of transformed foci. J Microsc 234:269–279PubMedGoogle Scholar
  588. US FDA (1995) Department of health and human services. Food additives; threshold of regulation for substances used in food-contact articles 21 CFR parts 5, 25, 170, 171, and 174Google Scholar
  589. US EPA, US Environmental Protection Agency (2004) In vitro dermal absorption rate testing of certain chemicals of interest to the occupational safety and health administration; final rule. Fed Register 69(80):22402–22441Google Scholar
  590. US EPA, US Environmental Protection Agency (2007a) Integrated summary report for the validation of an androgen receptor binding assay as a potential screen in the endocrine disruptor screening program. Accessed on 6 July 2010
  591. US EPA, US Environmental Protection Agency (2007b) Integrated summary report on aromatase. Accessed on 6 July 2010
  592. US EPA, US Environmental Protection Agency (2009) Integrated summary report for validation of an estrogen receptor binding assay using rat uterine cytosol as source of receptor as a potential screen in the endocrine disruptor screening program tier 1 battery. Accessed on 6 July 2010
  593. Vähäkangas K, Myllynen P (2006) Experimental methods to study human transplacental exposure to genotoxic agents. Mutat Res 608:129–135PubMedGoogle Scholar
  594. Van Calsteren V (2010) Analyse van de herhaalde toedieningstoxiciteitstesten met cosmetische ingrediënten op Europees niveau. Master thesis in pharmaceutical sciences. Dissertation, Vrije Universiteit BrusselGoogle Scholar
  595. Van Dartel DA, Pennings JL, Hendriksen PJ, van Schooten FJ, Piersma AH (2009) Early gene expression changes during embryonic stem cell differentiation into cardiomyocytes and their modulation by monobutyl phthalate. Reprod Toxicol 27:93–102PubMedGoogle Scholar
  596. Van Dartel DA, Pennings JL, van Schooten FJ, Piersma AH (2010) Transcriptomics-based identification of developmental toxicants through their interference with cardiomyocyte differentiation of embryonic stem cells. Toxicol Appl Pharmacol 243:420–428PubMedGoogle Scholar
  597. 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(1–2):17–33PubMedGoogle Scholar
  598. Van der Burg B, Winter R, Man HY, Vangenechten C, Berckmans P, Weimer M, Witters H, van der Linden S (2010a) Optimization and prevalidation of the in vitro AR CALUX method to test androgenic and antiandrogenic activity of compounds. Reprod Toxicol 30(1):18–24PubMedGoogle Scholar
  599. Van der Burg B, Winter R, Weimer M, Berckmans P, Suzuki G, Gijsbers L, Jonas A, van der Linden S, Witters H, Aarts J, Legler J, Kopp-Schneider A, Bremer S (2010b) Optimization and prevalidation of the in vitro ERalpha CALUX method to test estrogenic and antiestrogenic activity of compounds. Reprod Toxicol 30(1):73–80PubMedGoogle Scholar
  600. Van Leeuwen K, Schultz TW, Henry T, Diderich B, Veith GD (2009) Using chemical categories to fill data gaps in hazard assessment. SAR QSAR Environ Res 20:207–220PubMedGoogle Scholar
  601. van Loveren H, Cockshott A, Gebel T, Gundert-Remy U, de Jong WH, Matheson J, McGarry H, Musset L, Selgrade MK, Vickers C (2008) Skin sensitisation in chemical risk assessment: report of a WHO/IPCS international workshop focusing on dose–response assessment. Regul Toxicol Pharmacol 50(2):155–199PubMedGoogle Scholar
  602. Van Merris V, Van Wemmel K, Cortvrindt R (2007) In vitro effects of dexamethasone on mouse ovarian function and pre-implantation embryo development. Reprod Toxicol 23:32–41PubMedGoogle Scholar
  603. Van Och FM, Van Loveren H, Van Wolfswinkel JC, Machielsen AJ, Vandebriel RJ (2005) Assessment of potency of allergenic activity of low molecular weight compounds based on IL-1alpha and IL-18 production by a murine and human keratinocyte cell line. Toxicology 210(2–3):95–109PubMedGoogle Scholar
  604. Vandebriel RJ, van Loveren H (2010) Non-animal sensitisation testing: state-of-the-art. Crit Rev Toxicol 40(5):389–404PubMedGoogle Scholar
  605. Vanparys PH, Corvi R, Aardema M, Gribaldo L, Hayashi M, Hoffmann S, Schechtman L (2010) ECVAM prevalidation of three cell transformation assays. ALTEX 27:267–270Google Scholar
  606. Vedani A, Smiesko M (2009) In silico toxicology in drug discovery—concepts based on three-dimensional models. Altern Lab Anim 37:477–496PubMedGoogle Scholar
  607. Venkatapathy R, Moudgal CJ, Bruce RM (2004) Assessment of the oral rat chronic lowest observed adverse effect level model in TOPKAT, a QSAR software package for toxicity prediction. J Chem Inf Comput Sci 44(5):1623–1629PubMedGoogle Scholar
  608. Vermeire T, van de Bovenkamp M, de Bruin YB, Delmaar C, van Engelen J, Escher S, Marquat H, Meijster T (2010) Exposure-based waiving under REACH. Regul Toxicol Pharmacol 58(3):408–420PubMedGoogle Scholar
  609. Viravaidya K, Shuler ML (2004) Incorporation of 3T3-L1 cells to mimic bioaccumulation in a microscale cell culture analog device for toxicity studies. Biotechnol Prog 20:590–597PubMedGoogle Scholar
  610. Viravaidya K, Sin A, Shuler ML (2004) Development of a microscale cell culture analog to probe naphtalene toxicity. Biotechnol Prog 20:316–323PubMedGoogle Scholar
  611. Viswanath G, Halder S, Divya G, Majumder CB, Roy P (2008) Detection of potential (anti)progestagenic endocrine disruptors using a recombinant human progesterone receptor binding and transactivation assay. Mol Cell Endocrinol 295:1–9PubMedGoogle Scholar
  612. Vocanson M, Cluzel-Tailhardat M, Poyet G, Valeyrie M, Chavagnac C, Levarlet B, Courtellemont P, Rozières A, Hennino A, Nicolas JF (2008) Depletion of human peripheral blood lymphocytes in CD25+ cells allows for the sensitive in vitro screening of contact allergens. J Invest Dermatol 128(8):2119–2122PubMedGoogle Scholar
  613. Vocanson M, Hennino A, RoziŠres A, Poyet G, Nicolas JF (2009) Effector and regulatory mechanisms in allergic contact dermatitis. Allergy 64(12):1699–1714PubMedGoogle Scholar
  614. Wainford RD, Weaver RJ, Hawksworth GM (2009) The immediate early genes, c-fos, c-jun and AP-1, are early markers of platinum analogue toxicity in human proximal tubular cell primary cultures. Toxicol In Vitro 23(5):780–788PubMedGoogle Scholar
  615. Walsh MJ, Bruce SW, Pant K, Carmichael PL, Scott AD, Martin FL (2009) Discrimination of a transformation phenotype in Syrian golden hamster embryo (SHE) cells using ATR-FTIR spectroscopy. Toxicology 258:33–38PubMedGoogle Scholar
  616. Wang J, Hou T (2009) Recent advances on in silico ADME modeling. Annu Rep Comput Chem 5:101–127Google Scholar
  617. Wanner R, Sonnenburg A, Quatchadze M, Schreiner M, Peiser M, Zuberbier T, Stahlmann R (2010) Classification of sensitising and irritative potential in a combined in vitro assay. Toxicol Appl Pharmacol 245(2):211–218PubMedGoogle Scholar
  618. Waters NJ, Jones R, Williams G, Sohal B (2008) Validation of a rapid equilibrium dialysis approach for the measurement of plasma protein binding. J Pharmaceut Sci 97:4586–4595Google Scholar
  619. Waters MD, Jackson M, Lea I (2010) Characterizing and predicting carcinogenicity and mode of action using conventional and toxicogenomics methods. Mutat Res 705:184–200PubMedGoogle Scholar
  620. Webborn PJ, Parker AJ, Denton RL, Riley RJ (2007) In vitro-in vivo extrapolation of hepatic clearance involving active uptake: theoretical and experimental aspects. Xenobiotica 37:1090–1099PubMedGoogle Scholar
  621. Weed D (2005) Weight of evidence: a review of concept and methods. Risk Anal 25(6):1545–1557PubMedGoogle Scholar
  622. Weiland C, Ahr HJ, Vohr HW, Ellinger-Ziegelbauer H (2007) Characterization of primary rat proximal tubular cells by gene expression analysis. Toxicol In Vitro 21(3):466–491PubMedGoogle Scholar
  623. West PR, Weir AM, Smith AM, Donley EL, Cezar GG (2010) Predicting human developmental toxicity of pharmaceuticals using human embryonic stem cells and metabolomics. Toxicol Appl Pharmacol 247:18–27PubMedGoogle Scholar
  624. Westmoreland C, Carmichael P, Dent M, Fentem J, MacKay C, Maxwell G, Pease C, Reynolds F (2010) Assuring safety without animal testing: unilever’s ongoing research programme to deliver novel ways to assure consumer safety. Altex 27 special issue from the world congress on alternatives to animals, Rome, pp 61–65Google Scholar
  625. WHO, World Health Organisation (2008) World health statistics. Accessed 15 Jan 2011
  626. Widschwendter M, Jones PA (2002) DNA methylation and breast carcinogenesis. Oncogene 21:5462–5482PubMedGoogle Scholar
  627. Wieser M, Stadler G, Jennings P, Streubel B, Pfaller W, Ambros P, Riedl C, Katinger H, Grillari J, Grillari-Voglauer R (2008) hTERT alone immortalizes epithelial cells of renal proximal tubules without changing their functional characteristics. Am J Physiol Renal Physiol 295(5):F1365–F1375PubMedGoogle Scholar
  628. Wilding I, Bell J (2005) Improved early clinical development through human microdosing studies. Drug Discov Today 10(13):890–894Google Scholar
  629. Willemsen P, Scippo ML, Kausel G, Figueroa J, Maghuin-Rogister G, Martial JA, Muller M (2004) Use of reporter cell lines for detection of endocrine-disrupter activity. Anal Bioanal Chem 378:655–663PubMedGoogle Scholar
  630. Williams DP (2006) Toxicophores: investigations in drug safety. Toxicology 226:1–11PubMedGoogle Scholar
  631. Wilmes A, Crean D, Aydin S, Pfaller W, Jennings P, Leonard MO (2010) Identification and dissection of the Nrf2 mediated oxidative stress pathway in human renal proximal tubule toxicity. Toxicol In Vitro. doi: 10.1016/j.tiv.2010.12.009
  632. Winkler J, Sotiriadou I, Chen S, Hescheler J, Sachinidis A (2009) The potential of embryonic stem cells combined with -omics technologies as model systems for toxicology. Curr Med Chem 16:4814–4827PubMedGoogle Scholar
  633. Witters H, Freyberger A, Smits K, Vangenechten C, Lofink W, Weimer M, Bremer S, Ahr PH, Berckmans P (2010) The assessment of estrogenic or anti-estrogenic activity of chemicals by the human stably transfected estrogen sensitive MELN cell line: results of test performance and transferability. Reprod Toxicol 30(1):60–72PubMedGoogle Scholar
  634. Wolf T, Niehaus-Rolf C, Banduhn N, Eschrich D, Scheel J, Luepke NP (2008) The hen’s egg test for micronucleus induction (HET-MN): novel analyses with a series of well-characterized substances support the further evaluation of the test system. Mutat Res 650:150–164PubMedGoogle Scholar
  635. Woo YT, Lai DY (2003) Mechanisms of action of chemical carcinogens, and their role in structure–activity relationships (SAR) analysis and risk assessment. In: Benigni R (ed) Quantitative structure–activity relationship (QSAR) models of mutagens and carcinogens. CRC Press, Boca Raton, pp 41–80Google Scholar
  636. Woo YT, Lai DY, Argus MF, Arcos JC (1995) Development of structure–activity relationship rules for predicting carcinogenic potential of chemicals. Toxicol Lett 79:219–228PubMedGoogle Scholar
  637. 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 56:67–81PubMedGoogle Scholar
  638. Xu X, Yang W, Li Y, Wang YH (2010) Discovery of estrogen receptor modulators: a review of virtual screening and SAR efforts. Expert Opin Drug Discov 5:21–31Google Scholar
  639. Yan L, Sheihk-Bahaei S, Park S, Ropella GEP, Hunt CA (2008) Predictions of hepatic disposition properties using a mechanistically realistic, physiologically based model. Drug Metab Dispos 36:759–768PubMedGoogle Scholar
  640. Yang RSH, Thomas RS, Gustafson DL, Campain J, Benjamin SA, Verhaar HJM, Mumtaz MM (1998) Approaches to developing alternative and predictive toxicology based on PBPK/PD and QSAR modeling. Environ Health Perspect 106:1385–1393PubMedGoogle Scholar
  641. Zachow R, Uzumcu M (2006) The methoxychlor metabolite, 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane, inhibits steroidogenesis in rat ovarian granulosa cells in vitro. Reprod Toxicol 22:659–665PubMedGoogle Scholar
  642. Zaldívar JM, Mennecozzi M, Rodrigues R, Bouhifd M (2010) A biology-based dynamic approach for the modelling of toxicity in cell-based assays. Part I: fate modelling, EUR 24374 EN. European Commission, Joint Research Centre, LuxembourgGoogle Scholar
  643. Zanger UM, Turpeinen M, Klein K, Schwab M (2008) Functional Pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem 392(6):1093–1108PubMedGoogle Scholar
  644. Zeilinger K, Schreiter T, Darnell M, Lübberstedt M, Müller-Vieira U, Dillner B, Urbaniak T, Knobeloch D, Nüssler A, Gerlach JC, Andersson TB (2010) Human liver cell cultivation in a miniaturized 3D bioreactor system for in vitro studies on hepatic drug toxicity. ALTEX 27(suppl 2/10):148–149Google Scholar
  645. Zhang J, Musson DG (2006) Investigation of high-throughput ultrafiltration for the determination of an unbound compound in human plasma using liquid chromatography and tandem mass spectrometry with electrospray ionization. J Chromatogr B 843:47–56Google Scholar
  646. Zon LI, Peterson RT (2005) In vivo drug discovery in the zebrafish. Nat Rev Drug Discov 4:35–44PubMedGoogle Scholar
  647. Zuang V, Eskes C (2005) Alternative (non-animal) methods for cosmetics testing: current status and future prospects—a report prepared in the context of the 7th amendment of the cosmetic directive for establishing the timetable for phasing out animal testing—foreword. Atla Altern Lab Anim 33:1Google Scholar
  648. Zur Nieden NI, Ruf LJ, Kempka G, Hildebrand H, Ahr HJ (2001) Molecular markers in embryonic stem cells. Toxicol In Vitro 15:455–461PubMedGoogle Scholar
  649. Zur Nieden NI, Kempka G, Ahr HJ (2004) Molecular multiple endpoint embryonic stem cell test—a possible approach to test for the teratogenic potential of compounds. Toxicol Appl Pharmacol 194:257–269PubMedGoogle Scholar
  650. Zur Nieden NI, Davis LA, Rancourt DE (2010) Monolayer cultivation of osteoprogenitors shortens duration of the embryonic stem cell test while reliably predicting developmental osteotoxicity. Toxicology 277:66–73PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Sarah Adler
    • 1
  • David Basketter
    • 2
  • Stuart Creton
    • 3
  • Olavi Pelkonen
    • 4
  • Jan van Benthem
    • 5
  • Valérie Zuang
    • 6
    Email author
  • Klaus Ejner Andersen
    • 7
  • Alexandre Angers-Loustau
    • 6
  • Aynur Aptula
    • 8
  • Anna Bal-Price
    • 6
  • Emilio Benfenati
    • 9
  • Ulrike Bernauer
    • 10
  • Jos Bessems
    • 11
  • Frederic Y. Bois
    • 12
  • Alan Boobis
    • 13
  • Esther Brandon
    • 11
  • Susanne Bremer
    • 6
  • Thomas Broschard
    • 14
  • Silvia Casati
    • 6
  • Sandra Coecke
    • 6
  • Raffaella Corvi
    • 6
  • Mark Cronin
    • 15
  • George Daston
    • 16
  • Wolfgang Dekant
    • 17
  • Susan Felter
    • 18
  • Elise Grignard
    • 6
  • Ursula Gundert-Remy
    • 19
  • Tuula Heinonen
    • 20
  • Ian Kimber
    • 21
  • Jos Kleinjans
    • 22
  • Hannu Komulainen
    • 23
  • Reinhard Kreiling
    • 24
  • Joachim Kreysa
    • 6
  • Sofia Batista Leite
    • 6
    • 26
  • George Loizou
    • 27
  • Gavin Maxwell
    • 8
  • Paolo Mazzatorta
    • 25
  • Sharon Munn
    • 6
  • Stefan Pfuhler
    • 18
  • Pascal Phrakonkham
    • 6
  • Aldert Piersma
    • 5
  • Albrecht Poth
    • 28
  • Pilar Prieto
    • 6
  • Guillermo Repetto
    • 29
  • Vera Rogiers
    • 30
  • Greet Schoeters
    • 31
  • Michael Schwarz
    • 32
  • Rositsa Serafimova
    • 6
  • Hanna Tähti
    • 20
  • Emanuela Testai
    • 33
  • Joost van Delft
    • 22
  • Henk van Loveren
    • 22
    • 34
  • Mathieu Vinken
    • 30
  • Andrew Worth
    • 6
  • José-Manuel Zaldivar
    • 6
  1. 1.Centre for Documentation and Evaluation of Alternatives to Animal Experiments (ZEBET)Federal Institute for Risk Assessment (BfR)BerlinGermany
  2. 2.DABMEB Consultancy LtdSharnbrookUK
  3. 3.NC3RsLondonUK
  4. 4.Department of Pharmacology and ToxicologyUniversity of OuluOuluFinland
  5. 5.Laboratory for Health Protection ResearchNational Institute for Public Health and the Environment (RIVM)BilthovenThe Netherlands
  6. 6.ECVAM, Institute for Health & Consumer ProtectionEuropean Commission Joint Research CentreIspraItaly
  7. 7.Department of Dermatology and Allergy Centre, Odense University HospitalUniversity of Southern DenmarkOdenseDenmark
  8. 8.SEAC, UnileverColworth Science ParkSharnbrookUK
  9. 9.Laboratory of Environmental Chemistry and ToxicologyInstituto di Ricerche Farmacologiche “Mario Negri”MilanItaly
  10. 10.Federal Institute for Risk Assessment (BfR)BerlinGermany
  11. 11.Centre for Substances and Integrated Risk AssessmentNational Institute for Public Health and the Environment (RIVM)BilthovenThe Netherlands
  12. 12.Chair of Mathematical Modelling for Systems Toxicology, Compiegne and INERIS, DRC/VIVA/METOCompiegne University of TechnologyVerneuil en HalatteFrance
  13. 13.Imperial College LondonLondonUK
  14. 14.Merck KGaADarmstadtGermany
  15. 15.School of Pharmacy and Chemistry LiverpoolJohn Moores UniversityLiverpoolUK
  16. 16.Miami Valley Innovation CenterThe Procter and Gamble CompanyCincinnatiUSA
  17. 17.Department of ToxicologyJulius-Maximilians-Universität WürzburgWürzburgGermany
  18. 18.Procter and Gamble CompanyCentral Product SafetyCincinnatiUSA
  19. 19.Department ToxicologyMedical School (Charité)BerlinGermany
  20. 20.FICAM, School of MedicineUniversity of TampereTampereFinland
  21. 21.University of ManchesterManchesterUK
  22. 22.Department of Health Risk Analyses and Toxicology, Faculty of Health, Medicine and Life SciencesMaastricht UniversityMaastrichtThe Netherlands
  23. 23.Department of Environmental HealthNational Institute for Health and Welfare (THL)KuopioFinland
  24. 24.Clariant Produkte (Deutschland) GmbHSulzbachGermany
  25. 25.Nestlé Research CenterVers-chez-les-BlancLausanneSwitzerland
  26. 26.Instituto Tecnologia Química Biológica (ITQB)/Instituto Biologia Experimental (IBET)OeirasPortugal
  27. 27.Health and Safety Laboratory, Mathematical Sciences UnitHealth Improvement GroupHarpur Hill, BuxtonUK
  28. 28.Harlan Cytotest Cell Research GmbHRoßdorfGermany
  29. 29.University Pablo de OlavideSevillaSpain
  30. 30.Department of ToxicologyVrije Universiteit BrusselBrusselsBelgium
  31. 31.Department of Biomedical SciencesUniversity of AntwerpAntwerpBelgium
  32. 32.Institute of Pharmacology und ToxicologyUniversity of TuebingenTuebingenGermany
  33. 33.Istituto Superiore di SanitàRomeItaly
  34. 34.National Institute for Public Health and the Environment (RIVM), Laboratory for ToxicologyPathology and GeneticsBilthovenThe Netherlands

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