Skip to main content
SpringerLink
Log in

Regulatory toxicology in the twenty-first century: challenges, perspectives and possible solutions

Archives of Toxicology volume 89, pages 823–850 (2015)Cite this article

Abstract

The advent of new testing systems and “omics”-technologies has left regulatory toxicology facing one of the biggest challenges for decades. That is the question whether and how these methods can be used for regulatory purposes. The new methods undoubtedly enable regulators to address important open questions of toxicology such as species-specific toxicity, mixture toxicity, low-dose effects, endocrine effects or nanotoxicology, while promising faster and more efficient toxicity testing with the use of less animals. Consequently, the respective assays, methods and testing strategies are subject of several research programs worldwide. On the other hand, the practical application of such tests for regulatory purposes is a matter of ongoing debate. This document summarizes key aspects of this debate in the light of the European “regulatory status quo”, while elucidating new perspectives for regulatory toxicity testing.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Similar content being viewed by others

References

  • Abraham K, Mielke H, Huisinga W, Gundert-Remy U (2005) Elevated internal exposure of children in simulated acute inhalation of volatile organic compounds: effects of concentration and duration. Arch Toxicol 79(2):63–73

    CAS  PubMed  Google Scholar 

  • Adler S, Basketter D, Creton S, Pelkonen O, van Benthem J, Zuang V, Andersen KE, Angers-Loustau A, Aptula A, Bal-Price A, Benfenati E, Bernauer U, Bessems J, Bois FY, Boobis A, Brandon E, Bremer S, Broschard T, Casati S, Coecke S, Corvi R, Cronin M, Daston G, Dekant W, Felter S, Grignard E, Gundert-Remy U, Heinonen T, Kimber I, Kleinjans J, Komulainen H, Kreiling R, Kreysa J, Leite SB, Loizou G, Maxwell G, Mazzatorta P, Munn S, Pfuhler S, Phrakonkham P, Piersma A, Poth A, Prieto P, Repetto G, Rogiers V, Schoeters G, Schwarz M, Serafimova R, Tahti H, Testai E, van Delft J, van Loveren H, Vinken M, Worth A, Zaldivar JM (2011) Alternative (non-animal) methods for cosmetics testing: current status and future prospects—2010. Arch Toxicol 85:367–485

    CAS  PubMed  Google Scholar 

  • Aeby P, Ashikaga T, Bessou-Touya S, Schepky A, Gerberick F, Kern P, Marrec-Fairley M, Maxwell G, Ovigne JM, Sakaguchi H, Reisinger K, Tailhardat M, Martinozzi-Teissier S, Winkler P (2010) Identifying and characterizing chemical skin sensitizers without animal testing: Colipa’s research and method development program. Toxicol In Vitro 24(6):1465–1473

    CAS  PubMed  Google Scholar 

  • 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 sensitization risk assessment. Toxicol Sci 108(2):401–411

    CAS  PubMed  Google Scholar 

  • Alexander J, Benford D, Boobis A, Eskola M, Fink-Gremmels J, Fürst P, Heppner C, Schlatter J, van Leeuwen R (2012) Risk assessment of contaminants in food and feed. EFSA J 10(10):s1004–s1015

    Google Scholar 

  • Andrews PW, Benvenisty N, Knowles BB, McKay RD, Oh SK, Pera MF, Rossant J, Stacey GN (2010) Human ES cell lines—introduction. In Vitro Cell Dev Biol Anim 46(3–4):167–168

    PubMed  Google Scholar 

  • Anissimov YG, Jepps OG, Dancik Y, Roberts MS (2013) Mathematical and pharmacokinetic modelling of epidermal and dermal transport processes. Adv Drug Deliver Rev 65(2):169–190

    CAS  Google Scholar 

  • Arkin AP, Schaffer DV (2011) Innovations in 21st century systems biology. Cell 144(6):844–849

    CAS  PubMed  Google Scholar 

  • Arnot JA, Brown TN, Wania F, Breivik K, McLachlan MS (2012) Prioritizing chemicals and data requirements for screening-level exposure and risk assessment. Environ Health Perspect 120(11):1565–1570

    PubMed Central  PubMed  Google Scholar 

  • Astashkina A, Mann B, Grainger DW (2012) A critical evaluation of in vitro cell culture models for high-throughput drug screening and toxicity. Pharmacol Ther 134(1):82–106

    CAS  PubMed  Google Scholar 

  • Baker M (2011) Tissue models: a living system on a chip. Nature 471(7340):661–665

    CAS  PubMed  Google Scholar 

  • Balls M (1995) In vitro methods in regulatory toxicology: the crucial significance of validation. Arch Toxicol Suppl 17:155–162

    CAS  PubMed  Google Scholar 

  • Balshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R, Brozek J, Vist GE, Falck-Ytter Y, Meerpohl J, Norris S, Guyatt GH (2011) GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 64(4):401–406

    PubMed  Google Scholar 

  • Barbaric I, Gokhale PJ, Andrews PW (2010) High-content screening of small compounds on human embryonic stem cells. Biochem Soc Trans 38(4):1046–1050

    CAS  PubMed  Google Scholar 

  • Basketter DA, York M, McFadden JP, Robinson MK (2004) Determination of skin irritation potential in the human 4-h patch test. Contact Dermat 51(1):1–4

    CAS  Google Scholar 

  • Basketter D, Jirova D, Kandarova H (2012) Review of skin irritation/corrosion hazards on the basis of human data: a regulatory perspective. Interdisc Toxicol 5(2):98–104

    Google Scholar 

  • Bauch C, Kolle SN, Fabian E, Pachel C, Ramirez T, Wiench B, Wruck CJ, van Ravenzwaay B, Landsiedel R (2011) Intralaboratory validation of four in vitro assays for the prediction of the skin sensitizing potential of chemicals. Toxicol In Vitro 25(6):1162–1168

    CAS  PubMed  Google Scholar 

  • Benigni R, Bossa C, Giuliani A, Tcheremenskaia O (2010) Exploring in vitro/in vivo correlation: lessons learned from analyzing phase I results of the US EPA’s ToxCast project. J Environ Sci Health 28(4):272–286

    Google Scholar 

  • Bernauer U, Heinemeyer G, Heinrich-Hirsch B, Ulbrich B, Gundert-Remy U (2008) Exposure-triggered reproductive toxicity testing under the REACH legislation: a proposal to define significant/relevant exposure. Toxicol Lett 176(1):68–76

    CAS  PubMed  Google Scholar 

  • Bokkers BGH, Bakker MI, Boon PE, Bos P, Bosgra S, van der Heijden GWAM, Janer G, Slob W, van der Voet H (2009) The practicability of the integrated probabilistic risk assessment (IPRA) approach for substances in food. Bilthoven, Netherlands

    Google Scholar 

  • Borlak J (2009) 3,3-Trovafloxacin: a case study of idiosyncratic or iatrogenic liver toxicity–molecular mechanisms and lessons for pharmacotoxicity. Hum Exp Toxicol 28(2–3):119–121

    CAS  PubMed  Google Scholar 

  • Bourdon JA, Williams A, Kuo B, Moffat I, White PA, Halappanavar S, Vogel U, Wallin H, Yauk CL (2013) Gene expression profiling to identify potentially relevant disease outcomes and support human health risk assessment for carbon black nanoparticle exposure. Toxicology 303:83–93

    CAS  PubMed  Google Scholar 

  • Bowes J, Brown AJ, Hamon J, Jarolimek W, Sridhar A, Waldron G, Whitebread S (2012) Reducing safety-related drug attrition: the use of in vitro pharmacological profiling. Nat Rev Drug Discov 11(12):909–922

    CAS  PubMed  Google Scholar 

  • Bundesinstitut für Risikobewertung (2005) Risikobewertung genotoxischer und kanzerogener Stoffe soll in der EU harmonisiert werden. BfR-Stellungnahme 029/2005. http://www.bfr.bund.de/cm/343/risikobewertung_genotoxischer_und_kanzerogener_stoffe_soll_in_der_eu_harmonisiert_werden.pdf

  • Bundesministerium der Justiz (2005) Lebensmittel-, Bedarfsgegenstände- und Futtermittelgesetzbuch, Bundesrepublik Deutschland

  • Caldwell JC, Evans MV, Krishnan K (2012) Cutting edge PBPK models and analyses: providing the basis for future modeling efforts and bridges to emerging toxicology paradigms. J Toxicol 852384:1–10

    Google Scholar 

  • Carlin DJ, Rider CV, Woychik R, Birnbaum LS (2013) Unraveling the health effects of environmental mixtures: an NIEHS priority. Environ Health Perspect 121(1):a6–a8

    PubMed Central  PubMed  Google Scholar 

  • Chen LJ, Lian GP, Han LJ (2008) Use of “bricks and mortar” model to predict transdermal permeation: model development and initial validation. Ind Eng Chem Res 47(17):6465–6472

    CAS  Google Scholar 

  • Chipinda I, Hettick JM, Siegel PD (2011) Haptenation: chemical reactivity and protein binding. J Allergy 2011:839682

    Google Scholar 

  • Collins FS, Gray GM, Bucher JR (2008) Toxicology: transforming environmental health protection. Science 319(5865):906–907

    PubMed Central  CAS  PubMed  Google Scholar 

  • Combes R, Grindon C, Cronin MTD, Roberts DW, Garrod J (2007) Proposed integrated decision-tree testing strategies for mutagenicity and carcinogenicity in relation to the EU REACH legislation. Altern Lab Anim 35(2):267–287

    CAS  PubMed  Google Scholar 

  • Combes R, Grindon C, Cronin MTD, Roberts DW, Garrod JF (2008) Integrated decision-tree testing strategies for acute systemic toxicity and toxicokinetics with respect to the requirements of the EU REACH legislation. Altern Lab Anim 36(S1):91–109

    CAS  PubMed  Google Scholar 

  • Commission European (1993) European Parliament and Council Regulation (EC) No. 315/93 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006. OJ L37:1–3

    Google Scholar 

  • Commission European (1996) European Parliament and Council Regulation (EC) No. 2232/96 laying down a Community procedure for flavouring substances used or intended for use in or on foodstuffs. OJ L299:1–4

    Google Scholar 

  • Commission European (1997a) European Parliament and Council Regulation (EC) No. 258/97 concerning novel foods and novel food ingredients. OJ L43:1–6

    Google Scholar 

  • Commission European (1997b) European Parliament and Council Regulation (EC) No. 258/97 concerning the scientific aspects and the presentation of information necessary to support applications for the placing on the market of novel foods and novel food ingredients and the preparation of initial assessment reports under Regulation (EC) No 258/97 of the European Parliament and of the Council (Text with EEA relevance). OJ L253:1–36

    Google Scholar 

  • Commission European (1999) Comission decision 1999/217/EC adopting a register of flavouring substances used in or on foodstuffs drawn up in application of Regulation (EC) No. 2232/96 of the European Parliament and of the Council of 28 October 1996. OJ L84:1–137

    Google Scholar 

  • Commission European (2000) European Parliament and Council Regulation (EC) No. 1565/2000 laying down the measures necessary for the adoption of an evaluation programme in application of Regulation (EC) No. 2232/96 of the European Parliament and of the Council. OJ L180:8–16

    Google Scholar 

  • Commission European (2002a) European Parliament and Council Directive 2002/46/EC on the approximation of the laws of the Member States relating to food supplements. OJ L183:51–57

    Google Scholar 

  • Commission European (2002b) European Parliament and Council Regulation (EC) No. 178/2002 laying down the general principles and requirements of food law, establishing the European Food Safety Authority and laying down procedures in matters of food safety. OJ L31:1–24

    Google Scholar 

  • Commission European (2003a) European Parliament and Council Directive 2003/15/EC amending Council Directive 76/768/EEC on the approximation of the laws of the Member States relating to cosmetic products. OJ L66:26–35

    Google Scholar 

  • Commission European (2003b) European Parliament and Council Regulation (EC) No. 1829/2003 on genetically modified food and feed. OJ L268:1–23

    Google Scholar 

  • Commission European (2004) European Parliament and Council Regulation (EC) No 1935/2004 on materials and articles intended to come into contact with food and repealing Directives 80/590/EEC and 89/109/EEC. OJ L338:4–17

    Google Scholar 

  • Commission European (2005) European Parliament and Council Regulation (EC) No. 396/2005 on maximum residue levels of pesticides in or on food and feed of plant and animal origin and amending Council Directive 91/414/EEC. OJ L70:1–16

    Google Scholar 

  • Commission European (2006a) European Parliament and Council Directive 2006/118/EC on the protection of groundwater against pollution and deterioration. OJ L372:19–31

    Google Scholar 

  • Commission European (2006b) European Parliament and Council Regulation (EC) No. 1907/2006 concerning the registration, evaluation, authorization and restriction of chemials. OJ L396:1–849

    Google Scholar 

  • Commission European (2006c) European Parliament and Council Regulation (EC) No. 1925/2006 on the addition of vitamins and minerals and of certain other substances to foods. OJ L404:26–38

    Google Scholar 

  • Commission European (2008a) European Parliament and Council Regulation (EC) No. 1272/2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006. OJ L353:1–1355

    Google Scholar 

  • Commission European (2008b) European Parliament and Council Regulation (EC) No. 1331/2008 establishing a common authorization procedure for food additives, food enzymes and food flavourings. OJ L154:1–6

    Google Scholar 

  • Commission European (2008c) European Parliament and Council Regulation (EC) No. 1333/2008 on food additives. OJ L354:16–29

    Google Scholar 

  • Commission European (2008d) European Parliament and Council Regulation (EC) No. 1334/2008 on flavourings and certain food ingredients with flavouring properties for use in and on foods and amending Council Regulation (EEC) No. 1601/91, Regulations (EC) No 2232/96 and (EC) No. 110/2008 and Directive 2000/13/EC. OJ L354:34–50

    Google Scholar 

  • Commission European (2009a) European Parliament and Council Directive 2009/48/EC on the safety of toys. OJ L170:1–37

    Google Scholar 

  • Commission European (2009b) European Parliament and Council Regulation (EC) No. 1107/2009 concerning the placing of plant protection products on the market and repealing Council Directives 79/117/EEC and 91/414/EEC. OJ L230:1–50

    Google Scholar 

  • Commission European (2009c) European Parliament and Council Regulation (EC) No. 1223/2009 on cosmetic products. OJ L342:59–209

    Google Scholar 

  • Commission European (2011a) European Parliament and Council Regulation (EC) No. 544/2011 implementing Regulation (EC) No 1107/2009 of the European Parliament and of the Council as regards the data requirements for active substances. OJ L155:1–66

    Google Scholar 

  • Commission European (2011b) European Parliament and Council Regulation (EC) No. 545/2011 implementing Regulation (EC) No. 1107/2009 of the European Parliament and of the Council as regards the data requirements for plant protection products. OJ L155:67–126

    Google Scholar 

  • Commission European (2011c) European Parliament and Council Regulation (EC) No. 546/2011 implementing Regulation (EC) No 1107/2009 of the European Parliament and of the Council as regards uniform principles for evaluation and authorization of plant protection products. OJ L155:127–175

    Google Scholar 

  • Commission European (2012a) European Parliament and Council Regulation (EC) No. 528/2012 concerning the making available on the market and use of biocidal products. OJ L167:1–123

    Google Scholar 

  • Commission European (2012b) European Parliament and Council Regulation (EC) No. 872/2012 adopting the list of flavouring substances provided for by Regulation (EC) No 2232/96 of the European Parliament and of the Council, introducing it in Annex I to Regulation (EC) No 1334/2008 of the European Parliament and of the Council and repealing Commission Regulation (EC) No 1565/2000 and Commission Decision 1999/217/EC. OJ L267:1–161

    Google Scholar 

  • Commission European (2013a) Commission implementing regulation (EU) No. 503/2013 on applications for authorization of genetically modified food and feed in accordance with regulations (EC) No. 641/2004 and (EC) No. 1981/2006. OJ L157:1–47

    Google Scholar 

  • Commission European (2013b) European Parliament and Council Regulation (EC) No. 283/2013 setting out the data requirements for active substances, in accordance with Regulation (EC) No 1107/2009 of the European Parliament and of the Council concerning the placing of plant protection products on the market. OJ L93:1–84

    Google Scholar 

  • Commission European (2013c) European Parliament and Council Regulation (EC) No. 284/2013 setting out the data requirements for plant protection products, in accordance with Regulation (EC) No 1107/2009 of the European Parliament and of the Council concerning the placing of plant protection products on the market. OJ L93:85–152

    Google Scholar 

  • Cramer GM, Ford RA, Hall RL (1978) Estimation of toxic hazard-decision tree approach. Food Cosmet Toxicol 16(3):255–276

    CAS  PubMed  Google Scholar 

  • Dancik Y, Miller MA, Jaworska J, Kasting GB (2013) Design and performance of a spreadsheet-based model for estimating bioavailability of chemicals from dermal exposure. Adv Drug Deliver Rev 65(2):221–236

    CAS  Google Scholar 

  • de Wever B, Fuchs HW, Gaca M, Krul C, Mikulowski S, Poth A, Roggen EL, Vila MR (2012) Implementation challenges for designing integrated in vitro testing strategies (ITS) aiming at reducing and replacing animal experimentation. Toxicol In Vitro 26(3):526–534

    PubMed  Google Scholar 

  • Dorne JL, Renwick AG (2005) The refinement of uncertainty/safety factors in risk assessment by the incorporation of data on toxicokinetic variability in humans. Toxicol Sci 86(1):20–26

    CAS  PubMed  Google Scholar 

  • ECHA (2008) Guidance on information requirements and chemical safety assessment, Chapter R.6: QSARs and grouping of chemicals, Guidance Documents, European Chenicals Agency, Helsinki

  • ECHA (2011a) The operation of REACH and CLP, ECHA-11-R-003-EN. European Chemicals Agency, Helsinki

    Google Scholar 

  • ECHA (2011b) The use of alternatives to testing on animals for the REACH regulation, ECHA-11-1R-004.2-EN, European Chemicals Agency, Helsinki

  • ECHA (2012) Evaluation under REACH. Progress report, European Chemicals Agency, Helsinki

    Google Scholar 

  • EFSA (2004) Minutes of the 7th plenary meeting of the scientific panel on food additives, flavourings, processing aids and materials in contact with food. Brussels, Belgium

    Google Scholar 

  • EFSA (2005) Opinion of the scientific committee on a request from EFSA related to a harmonised approach for risk assessment of substances which are both genotoxic and carcinogenic. EFSA J 282:1–31

    Google Scholar 

  • EFSA (2006) Tolerable upper intake levels for vitamins and minerals. Brussels, Belgium

    Google Scholar 

  • EFSA (2007) The EFSA’s 7th scientific colloquium summary report—cumulative risk assessment of pesticides to human health: the way forward. Parma, Italy

    Google Scholar 

  • EFSA (2008) Guidance of the scientific committee on a request from EFSA related to uncertainties in dietary exposure assessment. EFSA J 704:1–84

    Google Scholar 

  • EFSA (2009) Scientific opinion on risk assessment for a selected group of pesticides from the triazole group to test possible methodologies to assess cumulative effects from exposure through food from these pesticides on human health. EFSA J 7(9):1167

    Google Scholar 

  • EFSA (2010a) Application of systematic review methodology to food and feed safety assessments to support decision making. EFSA J 8(6):1637

    Google Scholar 

  • EFSA (2010b) Guidance on the data required for the risk assessment of flavourings. EFSA J 8(6):1623

    Google Scholar 

  • EFSA (2011a) Scientific opinion on guidance for risk assessment of food and feed from genetically modified plants. EFSA J 9(5):2150

    Google Scholar 

  • EFSA (2011b) Scientific Opinion on the risks for animal and public health related to the presence of Alternaria toxins in feed and food. EFSA J 9(10):2407

    Google Scholar 

  • EFSA (2012a) Guidance for submission for food additive evaluations. EFSA J 10(7):2760

    Google Scholar 

  • EFSA (2012b) Guidance on the use of probabilistic methodology for modelling dietary exposure to pesticide residues. EFSA J 10(10):2839

    Google Scholar 

  • EFSA (2012c) Proposed template to be used in drafting scientific opinion on flavouring substances (explanatory notes for guidance included). EFSA J 10(1):218

    Google Scholar 

  • EFSA (2012d) Scientific opinion on evaluation of the toxicological relevance of pesticide metabolites for dietary risk assessment. EFSA J 10(7):2799

    Google Scholar 

  • EFSA (2012e) Scientific opinion on exploring options for providing advice about possible human health risks based on the concept of threshold of toxicological concern (TTC). EFSA J 10(7):2750

    Google Scholar 

  • EFSA (2013a) Scientific Opinion on the hazard assessment of endocrine disruptors: scientific criteria for identification of endocrine disruptors and appropriateness of existing test methods for assessing effects mediated by these substances on human health and the environment. EFSA J 11(3):3132–3216

    Google Scholar 

  • EFSA (2013b) Scientific opinion on the relevance of dissimilar mode of action and its appropriate application for cumulative risk assessment of pesticides residues in food. EFSA J 11(12):3472–3501

    Google Scholar 

  • Ellinger-Ziegelbauer H, Grnuender H, Brandenburg A, Ahr HJ (2008) Prediction of a carcinogenic potential of rat hepatocarcinogens using toxicogenomics analysis of short-term in vivo studies. Mutat Res 637(1–2):23–39

    CAS  PubMed  Google Scholar 

  • European Commission AXLR8. http://axlr8.eu/. Accessed 27 May 2013

  • European Commission SEURAT-1. http://www.seurat-1.eu/. Accessed 27 May 2013

  • European Commission Seventh Framework Programme (FP7). http://cordis.europa.eu/fp7/home_en.html. Accessed 27 May 2013

  • European Responsible Nutrition Alliance (ERNA), European Federation Association of Health Product Manufacturers (EHPM) (2004) Vitamin and mineral supplements: a risk management model, Brussels

  • Flynn A, Moreiras O, Stehle P, Fletcher RJ, Müller DJ, Rolland V (2004) Vitamins and minerals: a model for safe addition to foods. Eur J Nutr 42(2):118–130

    Google Scholar 

  • Garcia O, Carraro G, Navarro S, Bertoncello I, McQualter J, Driscoll B, Jesudason E, Warburton D (2012) Cell-based therapies for lung disease. Br Med Bull 101(1):147–161

    PubMed Central  CAS  PubMed  Google Scholar 

  • Garthoff B (1995) Alternative testing in drug research and development-the validation issue. Toxicol In Vitro 9(6):789–793

    CAS  PubMed  Google Scholar 

  • Georgopoulos PG, Sasso AF, Isukapalli SS, Lioy PJ, Vallero DA, Okino M, Reiter L (2009) Reconstructing population exposures to environmental chemicals from biomarkers: challenges and opportunities. J Expos Sci Environ Epidemiol 19(2):149–171

    CAS  Google Scholar 

  • Gilbert SF (2003) Developmental biology. Sinauer Associated, Sunderland

    Google Scholar 

  • Gomez-Lechon MJ, Lahoz A, Gombau L, Castell JV, Donato MT (2010) In vitro evaluation of potential hepatotoxicity induced by drugs. Curr Pharm Des 16(17):1963–1977

    CAS  PubMed  Google Scholar 

  • Greenland S (1987) Quantitative methods in the review of epidemiologic literature. Epidemiol Rev 9(1):1–30

    CAS  PubMed  Google Scholar 

  • Grogoryev Y (2013) Regulatory agency struggles under the weight of genomic data. Nat Med 19(4):385

    Google Scholar 

  • Gundert-Remy U, Mielke H, Bernauer U (2013) Commentary: dermal penetration of bisphenol A. Consequences for risk assessment. Toxicol Lett 217(2):159–161

    CAS  PubMed  Google Scholar 

  • Guzelian PS (1982) Comparative toxicology of chlordecone (Kepone) in humans and experimental animals. Annu Rev Pharmacol Toxicol 22:89–113

    CAS  PubMed  Google Scholar 

  • Hahn A (2009) Poison control centers. In: Wexler P, Gilbert SG, Hakkinen PJ, Mohapatra A (eds) Invormation resources in toxicology. Elsevier, Amsterdam, pp 701–710

    Google Scholar 

  • Hartung T (2009) Toxicology for the twenty-first century. Nature 460(7252):208–212

    CAS  PubMed  Google Scholar 

  • Hartung T, McBride M (2011) Food for thought… on mapping the human toxome. ALTEX 28(2):83–93

    PubMed  Google Scholar 

  • Hendriks HF (2013) Use of nutrigenomics endpoints in dietary interventions. Proc Nutr Soc 72:1–14

    Google Scholar 

  • Hoehme S, Brulport M, Bauer A, Bedawy E, Schormann W, Hermes M, Puppe V, Gebhardt R, Zellmer S, Schwarz M, Bockamp E, Timmel T, Hengstler JG, Drasdo D (2010) Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration. Proc Natl Acad Sci USA 107(23):10371–10376

    PubMed Central  CAS  PubMed  Google Scholar 

  • Höfer T, James D, Syversen T, Bowmer T (2011) Estimation of the acute hazard of chemicals based on route-to-route and endpoint extrapolation: experience from bulk maritime transport. Altern Lab Anim 39(6):541–556

    PubMed  Google Scholar 

  • Hoffmann S, Cole T, Hartung T (2005) Skin irritation: prevalence, variability, and regulatory classification of existing in vivo data from industrial chemicals. Regul Toxicol Pharmacol 41(3):159–166

    CAS  PubMed  Google Scholar 

  • Hoffmann S, Edler L, Gardner I, Gribaldo L, Hartung T, Klein C, Liebsch M, Sauerland S, Schechtman L, Stammati A, Nikolaidis E (2008) Points of reference in the validation process: the report and recommendations of ECVAM Workshop 66. Altern Lab Anim 36(3):343–352

    CAS  PubMed  Google Scholar 

  • Hoffmann SA, Müller-Vieira U, Biemel K, Knobeloch D, Heydel S, Lübberstedt M, Nüssler AK, Andersson TB, Gerlach JC, Zeilinger K (2012) Analysis of drug metabolism activities in a miniaturized liver cell bioreactor for use in pharmacological studies. Biotechnol Bioeng 109(12):3172–3181

    CAS  PubMed  Google Scholar 

  • Holzhutter HG, Drasdo D, Preusser T, Lippert J, Henney AM (2012) The virtual liver: a multidisciplinary, multilevel challenge for systems biology. Wires Syst Biol Med 4(3):221–235

    Google Scholar 

  • Hunter PJ, Crampin EJ, Nielsen PMF (2008) Bioinformatics, multiscale modeling and the IUPS physiome project. Brief Bioinform 9(4):333–343

    CAS  PubMed  Google Scholar 

  • Hwa AJ, Fry RC, Sivaraman A, So PT, Samson LD, Stolz DB, Griffith LG (2007) Rat liver sinusoidal endothelial cells survive without exogenous VEGF in 3D perfused co-cultures with hepatocytes. FASEB J 21(10):2564–2579

    CAS  PubMed  Google Scholar 

  • JECFA (1995) Evaluation of certain food additives and contaminants. Safety of flavouring agents. Forty-fourth report of the joint FAO/WHO expert committee on food additives. WHO Technical Report Series 859. World Health Organization, Geneva

  • JECFA (1996) Toxicological evaluation of certain food additives. Forty-fourth report of the joint FAO/WHO expert committee on food additives. WHO Technical Report Series 35. World Health Organization, Geneva

  • JECFA (1997) Evaluation of certain food additives and contaminants. Forty-sixth report of the joint FAO/WHO expert committee on food additives. WHO Technical Report Series 868. World Health Organization, Geneva

  • JECFA (1999) Evaluation of certain food additives and contaminants. Safety of flavouring agents. Forty-fourth report of the joint FAO/WHO expert committee on food additives. WHO Technical Report Series 884. World Health Organization, Geneva

  • Jennings P (2013) Stress response pathways, toxicity pathways and adverse outcome pathways. Arch Toxicol 87(1):13–14

    CAS  PubMed  Google Scholar 

  • Johansson H, Lindstedt M, Albrekt AS, Borrebaeck CA (2011) A genomic biomarker signature can predict skin sensitizers using a cell-based in vitro alternative to animal tests. BMC Genom 12(1):399

    CAS  Google Scholar 

  • Judson RS, Houck KA, Kavlock RJ, Knudsen TB, Martin MT, Mortensen HM, Reif DM, Rotroff DM, Shah I, Richard AM, Dix DJ (2010a) In vitro screening of environmental chemicals for targeted testing prioritization: the ToxCast project. Environ Health Perspect 118(4):485–492

    PubMed Central  CAS  PubMed  Google Scholar 

  • Judson RS, Martin MT, Reif DM, Houck KA, Knudsen TB, Rotroff M, Xia M, Sakamuru S, Huang R, Shinn P, Austin CP, Kavlock RJ, Dix DJ (2010b) Analysis of eight oil spill dispersants using rapid in vitro tests for endocrine and other biological activity. Environ Sci Technol 44(15):5979–5985

    PubMed Central  CAS  PubMed  Google Scholar 

  • Judson RS, Kavlock RJ, Setzer RW, Cohen Hubal EA, Martin MT, Knudsen TB, Houck KA, Thomas RS, Wetmore BA, Dix DJ (2011) Estimating toxicity-related biological pathway altering doses for high-throughput chemical risk assessment. Chem Res Toxicol 24(4):451–462

    CAS  PubMed  Google Scholar 

  • Judson R, Kavlock R, Martin M, Reif D, Houck K, Knudsen T, Richard A, Tice RR, Whelan M, Xia M, Huang R, Austin C, Daston G, Hartung T, Fowle JR, Wooge W, Tong W, Dix D (2013) Perspectives on validation of high-throughput assays supporting 21st century toxicity testing. ALTEX 30(1):51–66

    PubMed Central  PubMed  Google Scholar 

  • Kandárová H, Letašiová S (2011) Alternative methods in toxicology: pre-validated and validated methods. Interdisc Toxicol 4(3):107–113

    Google Scholar 

  • Kang KS, Trosko JE (2011) Stem cells in toxicology: fundamental biology and practical considerations. Toxicol Sci 120(Suppl 1):269–289

    Google Scholar 

  • Kavlock R, Dix D (2010) Computational toxicology as implemented by the U.S. EPA: providing high throughput decision support tools for screening and assessing chemical exposure, hazard and risk. J Toxicol Environ Health B Crit Rev 13(2–4):197–217

    CAS  PubMed  Google Scholar 

  • Kavlock R, Chandler K, Houck K, Hunter S, Judson R, Kleinstreuer N, Knudsen T, Martin M, Padilla S, Reif D, Richard A, Rotroff D, Sipes N, Dix D (2012) Update on EPA’s ToxCast program: providing high throughput decision support tools for chemical risk management. Chem Res Toxicol 25(7):1287–1302

    CAS  PubMed  Google Scholar 

  • Keller DA, Juberg DR, Catlin N, Farland WH, Hess FG, Wolf DC, Doerrer NG (2012) Identification and characterization of adverse effects in 21st century toxicology. Toxicol Sci 126(2):291–297

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kinsner-Ovaskainen A, Akkan Z, Casati S, Coecke S, Corvi R, Dal Negro G, De Bruijn J, De Silva O, Gribaldo L, Griesinger C, Jaworska J, Kreysa J, Maxwell G, McNamee P, Price A, Prieto P, Schubert R, Tosti L, Worth A, Zuang V (2009) Overcoming barriers to validation of non-animal partial replacement methods/integrated testing strategies: the report of an EPAA-ECVAM workshop. Altern Lab Anim 37(4):437–444

    CAS  PubMed  Google Scholar 

  • Kirouac DC, Saez-Rodriguez J, Swantek J, Burke JM, Lauffenburger DA, Sorger PK (2012) Creating and analyzing pathway and protein interaction compendia for modelling signal transduction networks. BMC Syst Biol 6(29):1–18

    Google Scholar 

  • Kloosterman J, Fransen HP, de Stoppelaar J, Verhagen H, Rompelberg C (2007) Safe addition of vitamins and minerals to foods: setting maximum levels for fortification in the Netherlands. Eur J Nutr 46(4):220–229

    PubMed Central  CAS  PubMed  Google Scholar 

  • Knight A (2008) Non-animal methodologies within biomedical research and toxicity testing. ALTEX 25(3):213–231

    PubMed  Google Scholar 

  • Knudsen TB, Houck KA, Sipes NS, Singh AV, Judson RS, Martin MT, Weissman A, Kleinstreuer NC, Mortensen HM, Reif DM, Rabinowitz JR, Setzer RW, Richard AM, Dix DJ, Kavlock RJ (2011) Activity profiles of 309 ToxCast chemicals evaluated across 292 biochemical targets. Toxicology 282(1–2):1–15

    CAS  PubMed  Google Scholar 

  • Kola I (2008) The state of innovation in drug development. Clin Pharmacol Ther 83(2):227–230

    CAS  PubMed  Google Scholar 

  • Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3(8):711–716

    CAS  PubMed  Google Scholar 

  • Kolle SN, Sullivan KM, Mehling A, van Ravenzwaay B, Landsiedel R (2012) Applicability of in vitro tests for skin irritation and corrosion to regulatory classification schemes: substantiating test strategies with data from routine studies. Regul Toxicol Pharmacol 64(3):402–414

    CAS  PubMed  Google Scholar 

  • Kortenkamp A, Evans R, Faust M, Kalberlah F, Scholze M, Schuhmacher-Wolz U (2012) Investigation of the state of the science on combined actions of chemicals in food through dissimilar modes of action and proposal for science-based approach for performing related cumulative risk assessment. Scientific Report submitted to EFSA Supporting Publications 2012:EN-232. www.efsa.europa.eu/publications

  • Kreienbrock L, Pigeot I, Ahrens W (2012) Epidemiologische Methoden. Spektrum Akademischer Verlag, Heidelberg

    Google Scholar 

  • Krewski D, Acosta D Jr, Andersen M, Anderson H, Bailar JC 3rd, 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(2–4):51–138

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kussmann M, Raymond F, Affolter M (2006) OMICS-driven biomarker discovery in nutrition and health. J Biotechnol 124(4):758–787

    CAS  PubMed  Google Scholar 

  • Liebsch M, Grune B, Seiler A, Butzke D, Oelgeschläger M, Pirow R, Adler S, Riebeling C, Luch A (2011) Alternatives to animal testing: current status and future perspectives. Arch Toxicol 85(8):841–858

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lilienblum W, Dekant W, Foth H, Gebel T, Hengstler JG, Kahl R, Kramer PJ, Schweinfurth H, Wollin KM (2008) Alternative methods to safety studies in experimental animals: role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH). Arch Toxicol 82(4):211–236

    CAS  PubMed  Google Scholar 

  • Linkov I, Bates ME, Canis LJ, Seager TP, Keisler JM (2011) A decision-directed approach for prioritizing research into the impact of nanomaterials on the environment and human health. Nat Nano 6(12):784–787

    CAS  Google Scholar 

  • Lock EF, Abdo N, Huang R, Xia M, Kosyk O, O’Shea SH, Zhou YH, Sedykh A, Tropsha A, Austin CP, Tice RR, Wright FA, Rusyn I (2012) Quantitative high-throughput screening for chemical toxicity in a population-based in vitro model. Toxicol Sci 126(2):578–588

    PubMed Central  CAS  PubMed  Google Scholar 

  • McKim JMJ, Wilga PC, Pregenzer JF, Petrella DK (2005) A biochemical approach to in vitro toxicity testing. Pharm Discov 5(1):30–36

    CAS  Google Scholar 

  • Meyer M, Schneckener S, Ludewig B, Kuepfer L, Lippert J (2012) Using expression data for quantification of active processes in physiologically-based pharmacokinetic modeling. Drug Metab Dispos 40:892–901

    CAS  PubMed  Google Scholar 

  • Mielke H, Gundert-Remy U (2012) Physiologically based toxicokinetic modelling as a tool to support risk assessment: three case studies. J Toxicol 2012:359471

    PubMed Central  PubMed  Google Scholar 

  • Mielke H, Abraham K, Gotz M, Vieth B, Lampen A, Luch A, Gundert-Remy U (2011a) Physiologically based toxicokinetic modelling as a tool to assess target organ toxicity in route-to-route extrapolation. The case of coumarin. Toxicol Lett 202(2):100–110

    CAS  PubMed  Google Scholar 

  • Mielke H, Anger LT, Schug M, Hengstler JG, Stahlmann R, Gundert-Remy U (2011b) A physiologically based toxicokinetic modelling approach to predict relevant concentrations for in vitro testing. Arch Toxicol 85(6):555–563

    CAS  PubMed  Google Scholar 

  • Mitragotri S, Anissimov YG, Bunge AL, Frasch HF, Guy RH, Hadgraft J, Kasting GB, Lane ME, Roberts MS (2011) Mathematical models of skin permeability: an overview. Int J Pharm 418(1):115–129

    CAS  PubMed  Google Scholar 

  • Naegel A, Hansen S, Neumann D, Lehr CM, Schaefer UF, Wittum G, Heisig M (2008) In-silico model of skin penetration based on experimentally determined input parameters. Part II: mathematical modelling of in vitro diffusion experiments. Identification of critical input parameters. Eur J Pharm Biopharm 68(2):368–379

    CAS  PubMed  Google Scholar 

  • Naegel A, Heisig M, Wittum G (2013) Detailed modeling of skin penetration. An overview. Adv Drug Deliver Rev 65(2):191–207

    CAS  Google Scholar 

  • National Research Council (2007) Toxicity testing in the 21st century: a vision and a strategy. The National Academies Press, Washington, DC

    Google Scholar 

  • Ochoa DJG, Bucher J, Pery AR, Zaldivar Comenges JM, Niklas J, Mauch K (2012) A multi-scale modeling framework for individualized, spatiotemporal prediction of drug effects and toxicological risk. Front Pharmacol 3:204

    Google Scholar 

  • OECD (2007) Guidance document on the validation of (quantitative) structure-activity relationship [(Q)SAR] models, Series on Testing and Assessment GD 69, Paris

  • OECD (2011) Report of the workshop on using mechanistic information in forming chemical categories. Organization for Economic Cooperation and Development, Paris

    Google Scholar 

  • OECD (2013) Guidance document on developing and assessing adverse outcome pathways. Series on Testing and Assessment GD 184, Paris

  • OECD OECDiLibrary. http://www.oecd-ilibrary.org. Accessed 27 May 2013

  • OECD The OECD QSAR Toolbox. http://www.oecd.org/env/ehs/risk-assessment/theoecdqsartoolbox.htm. Accessed 27 May 2013

  • Palmer RB, Brent J (2005) Derivation of a chemical-specific adjustment factor (CSAF) for use in the assessment of risk from chronic exposure to ethylene glycol: application of International Programme for Chemical Safety guidelines. Toxicol Appl Pharmacol 207(S2):576–584

    PubMed  Google Scholar 

  • Paparella M, Daneshian M, Hornek-Gausterer R, Kinzl M, Mauritz I, Mühlegger S (2013) Uncertainty of testing methods—what do we (want to) know? ALTEX 30(2):131–144

    PubMed  Google Scholar 

  • Patlewicz G, Roberts DW, Aptula A, Blackburn K, Hubesch B (2013) Workshop: use of “read-across” for chemical safety assessment under REACH. Regul Toxicol Pharmacol 65(2):226–228

    PubMed  Google Scholar 

  • Peiser M, Tralau T, Heidler J, Api AM, Arts JHE, Basketter DA, English J, Diepgen TL, Fuhlbrigge RC, Gaspari AA, Johansen JD, Karlberg AT, Kimber I, Lepoittevin JP, Liebsch M, Maibach HI, Martin SF, Merk HF, Platzek T, Rustemeyer T, Schnuch A, Vandebriel RJ, White IR, Luch A (2012) Allergic contact dermatitis: epidemiology, molecular mechanisms, in vitro methods and regulatory aspects. Cell Mol Life Sci 69(5):763–781

    PubMed Central  CAS  PubMed  Google Scholar 

  • Peter IS, Davidson EH (2011) Evolution of gene regulatory networks controlling body plan development. Cell 144(6):970–985

    PubMed Central  CAS  PubMed  Google Scholar 

  • Phillips BW, Crook JM (2010) Pluripotent human stem cells: a novel tool in drug discovery. BioDrugs 24(2):99–108

    CAS  PubMed  Google Scholar 

  • Phillips RD, Bahadori T, Barry BE, Bus JS, Gant TW, Mostowy JM, Smith C, Willuhn M, Zimmer U (2009) Twenty-first century approaches to toxicity testing, biomonitoring, and risk assessment: perspectives from the global chemical industry. J Expos Sci Environ Epidemiol 19(6):536–543

    CAS  Google Scholar 

  • Pugsley MK, Towart R, Authier S, Gallacher DJ, Curtis MJ (2011) Innovation in safety pharmacology testing. J Pharmacol Toxicol Methods 64(1):1–6

    CAS  PubMed  Google Scholar 

  • Rasmussen SE, Andersen NL, Dragsted LO, Larsen JC (2006) A safe strategy for addition of vitamins and minerals to foods. Eur J Nutr 45(3):123–135

    CAS  PubMed  Google Scholar 

  • Regot S, Macia J, Conde N, Furukawa K, Kjellén J, Peeters T, Hohmann S, de Nadal E, Posas F, Solé R (2010) Distributed biological computation with multicellular engineered networks. Nature 469(7329):207–211

    PubMed  Google Scholar 

  • Rim JE, Pinsky PM, van Osdol WW (2009) Multiscale modeling framework of transdermal drug delivery. Ann Biomed Eng 37(6):1217–1229

    PubMed  Google Scholar 

  • Rodricks JV, Levy JI (2013) Science and decisions: advancing toxicology to advance risk assessment. Toxikol Sci 131(1):1–8

    CAS  Google Scholar 

  • Rogiers V, Pauwels M (2008) Safety assessment of cosmetics in Europe, vol 36. S. Karger AG, Basel

    Google Scholar 

  • Rothman KJ, Greenland S, Lash TL (2008) Modern epidemiology. Lippincott Williams & Wilkins, Philadelphia

    Google Scholar 

  • Rovida C, Hartung T (2009) Re-evaluation of animal numbers and costs for in vivo tests to accomplish REACH legislation requirements for chemicals—a report by the transatlantic think tank for toxicology t(4). ALTEX 26(3):187–208

    PubMed  Google Scholar 

  • Sanco DG (2003) Guidance document on assessment of the relevance of metabolites in groundwater of substances regulated under council directive 91/414/EEC, Sanco/221/2000-rev 10 final, European Commission

  • Sasso AF, Isukapalli SS, Georgopoulos PG (2010) A generalized physiologically-based toxicokinetic modeling system for chemical mixtures containing metals. Theor Biol Med Model 7:17

    PubMed Central  PubMed  Google Scholar 

  • SCCS, SCHER, SCENIHR (2011) Toxicity and assessment of chemical mixtures—preliminary opinion approved for public consultation. http://ec.europa.eu/health/scientific_committees/environmental_risks/docs/scher_o_150.pdf

  • SCCS, SCHER, SCENIHR (2012a) Addressing the new challenges for risk assessment—discussion paper approved for public consultation in view of receiving feedback from stakeholders for its further development. SCCP ahead of print. http://ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_o_037.pdf

  • SCCS, SCHER, SCENIHR (2012b) Joint opinion on the use of the threshold of toxicological concern (TTC) approach for human safety assessment of chemical substances with focus on cosmetics and consumer products. SCCP 11171(08):1–56

  • Schanz J, Pusch J, Hansmann J, Walles H (2010) Vascularised human tissue models: a new approach for the refinement of biomedical research. J Biotechnol 148(1):56–63

    CAS  PubMed  Google Scholar 

  • Schenk B, Weimer M, Bremer S, van der Burg B, Cortvrindt R, Freyberger A, Lazzari G, Pellizzer C, Piersma A, Schäfer WR (2010) The ReProTect feasibility study, a novel comprehensive in vitro approach to detect reproductive toxicants. Reprod Toxicol 30(1):200–218

    CAS  PubMed  Google Scholar 

  • Schneider K, Schwarz M, Burkholder I, Kopp-Schneider A, Edler L, Kinsner-Ovaskainen A, Hartung T, Hoffmann S (2009) “ToxRTool”, a new tool to assess the reliability of toxicological data. Toxicol Lett 189(2):138–144

    CAS  PubMed  Google Scholar 

  • Schuster D, Laggner C, Langer T (2005) Why drugs fail—a study on side effects in new chemical entities. Curr Pharm Des 11(27):3545–3559

    CAS  PubMed  Google Scholar 

  • Seiler A, Oelgeschläger M, Liebsch M, Pirow R, Riebeling C, Adler S, Tralau T, Luch A (2011) Developmental toxicity testing in the 21st century: the sword of Damocles shattered by embryonic stem cell assays? Arch Toxicol 85:1361–1372

    CAS  PubMed  Google Scholar 

  • Simera I, Moher D, Hoey J, Schulz KF, Altman DG (2010) A catalogue of reporting guidelines for health research. Eur J Clin Invest 40(1):35–53

    CAS  PubMed  Google Scholar 

  • Song JJ, Ott HC (2011) Organ engineering based on decellularized matrix scaffolds. Trends Mol Med 17(8):424–432

    CAS  PubMed  Google Scholar 

  • Stevens JL, Baker TK (2009) The future of drug safety testing: expanding the view and narrowing the focus. Drug Discov Today 14(3–4):162–167

    PubMed  Google Scholar 

  • Tralau T, Luch A (2012a) Drug-mediated toxicity: illuminating the ‘bad’ in the test tube by means of cellular assays? Trends Pharmacol Sci 33(7):353–364

    CAS  PubMed  Google Scholar 

  • Tralau T, Luch A (2012b) “Drugs on oxygen”: an update and perspective on the role of cytochrome P450 testing in pharmacology. Expert Opin Drug Met 8(11):1357–1362

    CAS  Google Scholar 

  • Tralau T, Riebeling C, Pirow R, Oelgeschläger M, Seiler A, Liebsch M, Luch A (2012) Wind of change challenges toxicological regulators. Environ Health Perspect 120(11):1489–1494

    PubMed Central  PubMed  Google Scholar 

  • Tralau T, Sowada J, Luch A (2015) Insights on the human microbiome and its xenobiotic metabolism: what is known about its effects on human physiology? Expert Opin Drug Met 11(3):411–425

    CAS  Google Scholar 

  • Trosko JE, Chang CC (2010) Factors to consider in the use of stem cells for pharmaceutic drug development and for chemical safety assessment. Toxicology 270(1):18–34

    CAS  PubMed  Google Scholar 

  • Ullrich A, Stolz DB, Ellis EC, Strom SC, Michalopoulos GK, Hengstler JG, Runge D (2009) Long term cultures of primary human hepatocytes as an alternative to drug testing in animals. ALTEX 26(4):295–302

    PubMed  Google Scholar 

  • United Nations (2011a) Globally harmonized system of classification and labelling of chemicals (GHS). United Nations, New York

    Google Scholar 

  • United Nations (2011b) Recommendations on the transport of dangerous goods—model regulation. United Nations, New York

    Google Scholar 

  • US EPA Endocrine disruptor screening programme: ‘Universe of Chemicals and General Validation Principles’. www.epa.gov/endo/. Accessed 27 May 2013

  • US EPA ExpoCast. http://www.epa.gov/ncct/expocast/. Accessed 27 May 2013

  • US EPA Tox21. http://epa.gov/ncct/Tox21/. Accessed 27 May 2013

  • US EPA ToxCast. http://www.epa.gov/ncct/toxcast/. Accessed 27 May 2013

  • Uygun BE, Soto-Gutierrez A, Yagi H, Izamis M-L, Guzzardi MA, Shulman C, Milwid J, Kobayashi N, Tilles A, Berthiaume F, Hertl M, Nahmias Y, Yarmush ML, Uygun K (2010) Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med 16(7):814–820

    PubMed Central  CAS  PubMed  Google Scholar 

  • van der Jagt K, Munn S, Tørsløv J, de Bruijn J (2004) Alternative approaches can reduce the use of test animals under REACH. Report EUR 21405 EN, European Commission Joint Research Centre

  • Vanhaecke T, Snykers S, Rogiers V, Garthoff B, Castell JV, Hengstler JG (2009) EU research activities in alternative testing strategies: current status and future perspectives. Arch Toxicol 83(12):1037–1042

    CAS  PubMed  Google Scholar 

  • Werschkun B, Höfer T, Greiner M (2012) Emerging risks from ballast water treatment. BfR-Wissenschaft vol 08/2012. Federal Institute for Risk Assessment, Berlin

  • Wetmore BA, Wambaugh JF, Ferguson SS, Sochaski MA, Rotroff DM, Freeman K, Clewell HJ, Dix DJ, Andersen ME, Houck KA, Allen B, Judson RS, Singh R, Kavlock RJ, Richard AM, Thomas RS (2011) Integration of dosimetry, exposure and high-throughput screening data in chemical toxicity assessment. Toxicol Sci 125(1):157–174

    PubMed  Google Scholar 

  • Whitebread S, Hamon J, Bojanic D, Urban L (2005) Keynote review: in vitro safety pharmacology profiling: an essential tool for successful drug development. Drug Discov Today 10(21):1421–1433

    CAS  PubMed  Google Scholar 

  • WHO (2005) Chemical specific adjustment factors for interspecies differences and human variability. Guidance document for use of data in dose/concentration—response assessment. WHO, Geneva

  • WHO (2009) Uncertainty and data quality in exposure assessment, Harmonization Project Document No. 6. http://www.who.int/ipcs/publications/methods/harmonization/exposure_assessment.pdf?ua=1

  • WHO (2014) Guidance document on evaluating and expressing uncertainty in hazard characterization. Harmonization Project Document No. 11. http://www.who.int/ipcs/methods/harmonization/uncertainty_in_hazard_characterization.pdf?ua=1

  • Wiesinger M, Mayer B, Jennings P, Lukas A (2012) Comparative analysis of perturbed molecular pathways identified in in vitro and in vivo toxicology studies. Toxicol In Vitro 26(6):956–962

    CAS  PubMed  Google Scholar 

  • Williams PA, Cosme J, Ward A, Angove HC, Matak Vinkovic D, Jhoti H (2003) Crystal structure of human cytochrome P450 2C9 with bound warfarin. Nature 424(6947):464–468

    CAS  PubMed  Google Scholar 

  • Wilson VS, Keshava N, Hester S, Segal D, Chiu W, Thompson CM, Euling SY (2011) Utilizing toxicogenomic data to understand chemical mechanism of action in risk assessment. Toxicol Appl Pharmacol. doi:10.1016/j.taap.2011.01.017)

    Google Scholar 

  • 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(36):4814–4827

    CAS  PubMed  Google Scholar 

  • Wobus AM, Loser P (2011) Present state and future perspectives of using pluripotent stem cells in toxicology research. Arch Toxicol 85(2):79–117

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wölfle D, Pfaff K (2010) Sicherheitsbewertung von Materialien im Kontakt mit Lebensmitteln. Bundesgesundheitsblatt 53(6):561–566

    Google Scholar 

  • Yildirimman R, Brolen G, Vilardell M, Eriksson G, Synnergren J, Gmuender H, Kamburov A, Ingelman-Sundberg M, Castell J, Lahoz A, Kleinjans J, van Delft J, Bjorquist P, Herwig R (2011) Human embryonic stem cell derived hepatocyte-like cells as a tool for in vitro hazard assessment of chemical carcinogenicity. Toxicol Sci 124(2):278–290

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zeiger E, Hoffmann GR (2012) An illusion of hormesis in the Ames test: statistical significance is not equivalent to biological significance. Mutat Res 746(1):89–93

    CAS  PubMed  Google Scholar 

  • Zurlo J (2012) No animals harmed: toward a paradigms shift in toxicity testing. The Hastings Center Report 42(1):23–26

    Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge the input gained from numerous critical discussions with colleagues at the BfR.

Author information

Authors and Affiliations

  1. German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, 10589, Berlin, Germany

    Tewes Tralau, Michael Oelgeschläger, Rainer Gürtler, Gerhard Heinemeyer, Matthias Herzler, Thomas Höfer, Heike Itter, Thomas Kuhl, Nikola Lange, Nicole Lorenz, Christine Müller-Graf, Ulrike Pabel, Ralph Pirow, Vera Ritz, Helmut Schafft, Heiko Schneider, Thomas Schulz, David Schumacher, Sebastian Zellmer, Gaby Fleur-Böl, Matthias Greiner, Monika Lahrssen-Wiederholt, Alfonso Lampen, Andreas Luch, Gilbert Schönfelder, Roland Solecki, Reiner Wittkowski & Andreas Hensel

Authors
  1. Tewes Tralau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Oelgeschläger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rainer Gürtler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gerhard Heinemeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matthias Herzler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas Höfer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Heike Itter
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Thomas Kuhl
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nikola Lange
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nicole Lorenz
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Christine Müller-Graf
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ulrike Pabel
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ralph Pirow
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Vera Ritz
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Helmut Schafft
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Heiko Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Thomas Schulz
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. David Schumacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Sebastian Zellmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Gaby Fleur-Böl
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Matthias Greiner
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Monika Lahrssen-Wiederholt
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Alfonso Lampen
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Andreas Luch
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Gilbert Schönfelder
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Roland Solecki
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Reiner Wittkowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Andreas Hensel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andreas Luch.

Additional information

Tewes Tralau and Michael Oelgeschläger are first authors.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tralau, T., Oelgeschläger, M., Gürtler, R. et al. Regulatory toxicology in the twenty-first century: challenges, perspectives and possible solutions. Arch Toxicol 89, 823–850 (2015). https://doi.org/10.1007/s00204-015-1510-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-015-1510-0

Keywords

search

Navigation