Metabolism: A Bottleneck in In Vitro Toxicological Test Development

Klaassen C.D. , ed. (2001). Casarett & Doull's Toxicology: The Basic Science of Poisons, 6th edn, p. 1236. New York, NY, USA: McGraw-Hill.

Lewis D.F.V. (1996). Cytochromes P450, Structure, Function and Mechanism, 348 pp. London, UK: Taylor & Francis.

Crespi C.L. (1995). Xenobiotic-metabolizing human cells as tools for pharmacological and toxicological research. Advances in Drug Research 26, 179–235.

Cashman J.R. (2004). The implications of polymorphisms in mammalian flavin-containing monooxygenases in drug discovery and development. Drug Discovery Today 9, 574–581.

Hayes J.D. , Flanagan J.U. , & Jowsey I.R. (2004). Glutathione transferases. Annual Reviews of Pharmacology and Toxicology 45, 51–88.

Ioannides C. , ed. (2002). Enzyme Systems that Metabolise Drugs and Other Xenobiotics, pp. 1–32. Chichester, UK: John Wiley & Sons.

Glatt H. (2000). Sulfotransferases in the bioactivation of xenobiotics. Chemico-Biological Interactions 129, 141–170.

Phillips I.R. , & Shephard E.A. , eds. (1998). Cytochrome P450 Protocols. Methods in Molecular Biology 107, 439–468.

Castell J.V. , & Gómez-Lechón M.J. , eds. (1997). In vitro Methods in Pharmaceutical Research. 467 pp. London, UK: Academic Press.

Plant N. (2003). Strategies for using in vitro screens in drug metabolism. Drug Discovery Today 9, 328–336.

Ekins S. (2000). Present and future in vitro approaches for drug metabolism. Journal of Pharmacological and Toxicological Methods 44, 313–324.

Anon. (2005). Cytochrome P450 isoform-specific in vitro methods to predict drug metabolism and interactions. Website http://herkules.oulu.fi/isbn9514259009/html/i412429.html (Accessed 12.07.05).

Kim R.B. (2002). Transporters and xenobiotic disposition. Toxicology 181-182, 291–297.

Combes R.D. (2004). The case for taking account of metabolism when testing for potential endocrine disruptors in vitro. ATLA 32, 121–135.

Ioannides C. , & Lewis D.F. (2004). Cytochromes P450 in the bioactivation of chemicals. Current Topics in Medicinal Chemistry 4, 1767–1788.

Bailey M.J. , & Dickinson R.G. (2003). Acyl glucuronide reactivity in perspective: biological consequences. Chemico-Biological Interaction 145, 117–137.

Anders M.W. (2004). Glutathione-dependent bioactivation of haloalkanes and haloalkenes. Drug Metabolism Reviews 36, 583–594.

Banoglu E. (2000). Current status of the cytosolic sulfotransferases in the metabolic activation of promutagens and procarcinogens. Current Drug Metabolism 1, 1–30.

Morisseau C. , & Hammock B.D. (2004). Epoxide hydrolases: mechanisms, inhibitor designs and biological roles. Annual Reviews of Pharmacology and Toxicology 45, 311–333.

Deckers-Schmelzle B. , Klaus E. , Kahl R. , & Kahl G.F. (1978). Binding of benzo(a)pyrene metabolites to cellular DNA in perfused rat lungs. Naunyn-Schmiedeberg's Archives of Pharmacology 303, 303–307.

Kadlubar F.F. , Butler M.A. , Kaderlik K.R. , Chou H.C. , & Lang N.P. (1992). Polymorphisms for aromatic amine metabolism in humans: relevance for human carcinogenesis. Environmental Health Perspectives 98, 69–74.

Turesky R.J. , Lang N.P. , Butler M.A. , Teitel C.H. , & Kadlubar F.F. (1991). Metabolic activation of carcinogenic heterocyclic aromatic amines by human liver and colon. Carcinogenesis 12, 1839–1845.

Timchalk C. , Nolan R.J. , Mendrala A.L. , Sittenber D.A. , Brzak K.A. , & Mattsson J.L. (2002). A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for the organophosphate insecticide chlorpyrifos in rats and humans. Toxicological Sciences 66, 34–53.

Poet T.S. , Kousba A.A. , Dennison S.L. , & Timchalk C. (2004). Physiologically based pharmacokinetic/pharmacodynamic model for the organo-phosphorus pesticide diazinon. Neurotoxicology 25, 1013–1030.

Jones D.C. , Duvauchelle C. , Ikegami A. , Olsen C.M. , Lau S.S. , de la Torre R. , & Monks T.J. (2005). Serotonergic neurotoxic metabolites of ecstasy identified in rat brain. Journal of Pharmacology and Experimental Therapeutics 313, 422–431.

Hotchkiss S.A.M. (1992). Skin as a xenobiotic metabolizing organ. In Progress in Drug Metabolism, Vol. 13 (ed. Gibson G.G. ), pp. 217–262. London, UK: Taylor & Francis.

Howes D. , Guy R. , Hadgraft J. , Heylings J. , Hoeck U. , Kemper F. , Maibach H. , Marty J-P. , Merk H. , Parra J. , Rekkas D. , Rondelli I. , Schaefer H. , Täuber U. , & Verbiese N. (1996). Methods for assessing percutaneous absorption. The report and recommendations of ECVAM workshop 13. ATLA 24, 81–106.

Skalova L. , Szotakova B. , Wsol V. , Kral R. , Baliharova V. , & Lamka J. (2000). Activity, stereospecificity, and stereoselectivity of microsomal enzymes in dependence on storage and freezing of rat liver samples. Chirality 12, 649–653.

Combes R.D. (1992). The in vivo relevance of in vitro genotoxicity assays incorporating enzyme activation systems. In Progress in Drug Metabolism, Vol. 13 (ed. Gibson G.G. ), pp. 295–321. London, UK: Taylor & Francis.

Hall P.M. , Stupans I. , Burgess W. , Birkett D.J. , & McManus M.E. (1989). Immunohistochemical localization of NADPH-cytochrome P450 reductase in human tissues. Carinogenesis 10, 521–530.

Windmill K.F. , Gaedigk A. , Hall P.M. , Samaratunga H. , Grant D.M. , & McManus M.E. (2000). Localization of N-acetyltransferases NAT1 and NAT2 in human tissues. Toxicological Sciences 54, 19–29.

Ding X. , & Kiaminsky L.S. (2003). Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue toxicity in the respiratory and gastrointestinal tracts. Annual Reviews of Pharmacology and Toxicology 43, 149–173.

Pelkonen O. , & Raunio H. (1997). Metabolic activation of toxins: tissue-specific expression and metabolism in target organs. Environmental Health Perspectives 105, 767–774.

Ullrich A.B. , Standop J. , Schmied B.M. , Schneider M.B. , Lawson T.A. , & Pour P.M. (2002). Species differences in the distribution of drug-metabolizing enzymes in the pancreas. Toxicologic Pathology 30, 247–253.

Minn A. , Ghersi-Egea J.F. , Perrin R. , Leininger B. , & Siest G. (1991). Drug metabolizing enzymes in the brain and cerebral microvessels. Brain Research Reviews 16, 65–82.

Strazielle N. , & Ghersi-Egea J.F. (2000). Implication of blood–brain interfaces in cerebral drug metabolism and drug metabolite disposition. In Molecular Drug Metabolism and Toxicology (eds Williams G. , & Aruoma O.I. ), pp. 181–200. London, UK: OICA International.

Miksys S. , & Tyndale R.F. (2004). The unique regulation of brain cytochrome P450 2 (CYP2) family enzymes by drugs and genetics. Drug Metabolism Reviews 36, 313–333.

Gaylor D.W. , & Zheng Q. (1996). Risk assessment of nongenotoxic carcinogens based upon cell proliferation/death rates in rodents. Risk Analysis 16, 221–225.

Goeptar A.R. , Commandeur J.N.M. , van Ommen B. , Van Bladeren P.J. , & Vermeulen N.P.E. (1995). Metabolism and kinetics of trichloroethylene in relation to toxicity and carcinogenicity. Relevance of mercapturic acid pathway. Chemical Research in Toxicology 8, 3–21.

Teissier E. , Fennrich S. , Strazielle N. , Daval J-L. , Ray D. , Schlosshauer B. , & Ghersi-Egea J-F. (1998). Drug metabolism in in vitro organotypic and cellular models of mammalian central nervous system: activities of membrane-bound epoxide hydrolase and NADPH-cytochrome P450 (c) reductase. Neurotoxicology 19, 347–356.

Dahl M.L. , & Bertilsson L. (1993). Genetically variable metabolism of antidepressants and neuroleptic drugs in man. Pharmacogenetics 3, 61–70.

Evans W.E. , & Relling M.V. (1999). Pharmacogenomics: translating functional genomics into rational therapeutics. Science, New York 286, 487–491.

Kalow W. , & Tyndale R.F. (1992). Debrisoquine/sparteine monoxygenase and other P450s in the brain. In Pharmacogenetics of Drug Metabolism (ed. Kalow W. ), pp. 649–656. New York, NY, USA: Pergamon Press.

Gervasini G. , Carrillo J.A. , & Benitez J. (2004). Potential role of cerebral cytochrome P450 in clinical pharmacokinetics. Clinical Pharmacokinetics 43, 693–706.

Monks T.J. , Ghersi-Egea J.F. , Philbert M. , Cooper A.J. , & Lock E.A. (1999). Symposium overview: the role of glutathione in neuroprotection and neurotoxicity. Toxicological Sciences 51, 161–177.

Strazielle N. , Khuth S.T. , & Ghersi-Egea J.F. (2004). Detoxification systems, passive and specific transport for drugs at the blood-CSF barrier in normal and pathological situations. Advanced Drug Delivery Reviews 56, 1717–1740.

Henderson C.J. , & Wolf C.R. (2003). Transgenic analysis of human drug-metabolizing enzymes: pre-clinical drug development and toxicology. Molecular Interventions 3, 331–343.

Gonzalez F. (2004). Cytochrome P450 humanised mice. Human Genomics 1, 300–306.

Bigger C.A.H. , Tomaszewski J.E. , Dipple A. , & Lake R.S. (1980). Limitations of metabolic activation systems used with in vitro tests for carcinogens. Science, New York 209, 503–505.

Parkinson C. , & Grasso P. (1993). The use of the dog in toxicity tests on pharmaceutical compounds. Human and Experimental Toxicology 2, 99–109.

Beasley V. (1999). Absorption, distribution, metabolism, and elimination: differences among species. In Veterinary Toxicology (ed. Beasley V. ), 21 pp. Ithaca, NY, USA: International Veterinary Information Service. Website http://www.ivis.org/advances/Beasley/AppC/chapter_frm.asp?LA=1#3 (Accessed 30.09.05).

Pacifici G.M. , & Pelkonen O. , eds. (2001). Inter-individual Variability in Human Drug Metabolism, pp. 358–394. London, UK: Taylor & Francis.

Pelkonen O. , Mäenpää J. , Taavitsainen P. , Rautio A. , & Raunio H. (1998). Inhibition and induction of human cytochrome P450 (CYP) enzymes. Xenobiotica 28, 1203–1253.

Ingelman-Sundberg M. (2004). Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms. Naunyn-Schmiedeberg's Archives of Pharmacology 369, 89–104.

Rendic S. (2002). Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metabolism Reviews 34, 83–448.

Rogiers V. , Coecke S. , Vandenberghe Y. , Morel F. , Callaerts A. , Verleye G. , Van Bezooijen C.F. , Guillouzo A. , & Vercruysse A. (1991). Effect of the ageing process on the gender and phenobarbital dependent expression of glutathione S-transferase subunits in brown Norway rat liver. Biochemical Pharmacology 42, 491–498.

Coecke S. , Vandenberghe Y. , Callaerts A. , Sonck W. , Verleye G. , Van Bezooijen C.F. , Vercruysse A. , & Rogiers V. (1990). Hepatic cytosolic glutathione S-transferase activities in ageing brown Norway rats — importance of sex differences and phenobarbital treatment for studies of ageing. Mechanisms of Ageing and Development 55, 189–198.

Ade P. , Guastadisegni C. , Testai E. , & Vittozzi L. (1994). Multiple activation of CHCl₃ in kidney microsomes from male and female DBA/2J mice. Journal of Biochemical Toxicology 9, 289–295.

Kimura S. , Donovan J.C. , & Nebert D.W. (1987). Expression of the mouse P₁450 gene during differentiation without foreign chemical stimulation. Journal of Experimental Pathology 3, 61–74.

Miller M.S. , Juchau M.R. , Guengerich F.P. , Nebert D.W. , & Raucy J.L. (1996). Drug metabolic enzymes in developmental toxicology. Fundamental and Applied Toxicology 34, 165–176.

Morgan E.T. (2001). Regulation of cytochrome P450 by inflammatory mediators. Drug Metabolism and Disposition 29, 207–212.

Baillie T.A. , Cayen M.N. , Fouda H. , Gerson R.J. , Green J.D. , Grossman S.J. , Klunk L.J. , Le Blanc B. , Perkins D.G. , & Shipley L.A. (2002). Contemporary issues in toxicology. Toxicology and Applied Pharmacology 182, 188–196.

Williams D.P. , & Park B.K. (2003). Idiosyncratic toxicity: the role of toxicophores and bioactivation. Drug Discovery Today 8, 1044–1050.

Lin J.H. , & Lu A.Y.H. (1997). Role of pharmacokinetics and metabolism in drug discovery and development. Pharmacological Reviews 49, 403–449.

Leahy D.E. , Duncan R. , Ahr H.J. , Bayliss M.K. , de Boer A.G. , Darvas F. , Fentem J.H. , Fry J.R. , Hopkins R. , Houston J.B. , Karlsson J. , Kedderis G.L. , Pratten M.K. , Prieto P. , Smith D.A. , & Straughan D.W. (1997). Pharmacokinetics in early drug research. The report and recommendations of ECVAM Workshop 22. ATLA 25, 17–31.

Van de Waterbeemd H. , & Gifford E. (2003). ADMET in silico modelling: towards prediction paradise? Nature Reviews — Drug Discovery 2, 192–204.

Worth A.P. , & Balls M. , eds. (2002). Alternative (non-animal) methods for chemicals testing: current status and future prospects. A report prepared by ECVAM and the ECVAM Working Group on Chemicals. ATLA 30, Suppl. 1, 1–125.

Spielmann H. , & Liebsch M. (2002). Validation successes: chemicals. ATLA 30, Suppl. 2, 33–40.

De Silva O. , Basketter D.A. , Barratt M.D. , Corsini E. , Cronin M.T.D. , Das P.K. , Degwert J. , Enk A. , Garrigue J.L. , Hauser C. , Kimber I. , Lepoittevin J-P. , Peguet J. , & Ponec M. (1995). Alternative methods for skin sensitisation testing: the report and recommendations of ECVAM workshop 19. ATLA 24, 683–705.

Kimber I. (2000). Skin sensitisation: immunological mechanisms and novel approaches to predictive testing. In Progress in the Reduction, Refinement and Replacement of Animal Experimentation (ed. Balls M. , van Zeller A-M. , & Halder M.E. ), pp. 613–622. Amsterdam, The Netherlands: Elsevier.

Casati S. , Aeby P. , Basketter D.A. , Cavani A. , Gennari A. , Gerberick G.F. , Griem P. , Hartung T. , Kimber I. , Lepoittevin J-P. , Meade B.J. , Pallardy M. , Rougier N. , Rousset F. , Rubinstenn G. , Sallusto F. , Verheyen G.R. , & Zuang V. (2005). Dendritic cells as a tool for the predictive identification of skin sensitisation hazard. The report and recommendations of ECVAM Workshop 51. ATLA 33, 47–62.

Coecke S. , Eskes C. , Gartlon J. , Kinsner A. , Price A. , van Vliet E. , Prieto P. , Boveri M. , Pellizzer C. , Wendel A. , & Hartung T. (2005). The value of alternative testing for neurotoxicity in the context of regulatory needs. Environmental Toxicology and Pharmacology, in press.

Park B.K. , Kitteringham N.R. , Maggs J.L. , Pirmohamed M. , & Williams D.P. (2005). The role of metabolic activation in drug-induced hepatotoxicity. Annual Reviews of Pharmacology and Toxicology 45, 177–202.

Zucco F. , De Angelis I. , Testai E. , & Stammati A. (2003). Toxicology investigations with cell culture systems: 20 years after. Toxicology in Vitro 18, 15–163.

Lee Y.C. , Shlyankevich M. , Jeong H.K. , Douglas J.S. , & Surh Y.J. , (1995). Bioactivation of 5-hydroxylmethyl-2-furaldehyde to an electrophilic and mutagenic allylic sulfuric acid ester. Biochemical and Biophysical Research Communications 209, 996–1002.

Bogni A. , Monshouwer M. , Moscone A. , Hidestrand M. , Ingelman-Sundberg M. , Hartung T. , & Coecke S. (2005). Substrate specific metabolism by polymorphic cytochrome P450 2D6 alleles. Toxicology in Vitro 19, 621–629.

Coecke S. , Bogni A. , Langezaal I. , Worth A. , Hartung T. , & Monshouwer M. (2001). The use of genetically engineered cells for assessing CYP2D6-related polymorphic effects. Toxicology in Vitro 15, 553–556.

Glatt H. , Gemperlein I. , Turchi G. , Heinritz H. , Doehmer J. , & Oesch F. (1988). Search for cell culture systems with diverse xenobiotic-metabolizing activities and their use in toxicological studies. Molecular Toxicology 1, 313–334.

Freshney I.R. (2000). Culture of Animal Cells: A Manual of Basic Techniques, 4th edn, 608 pp. Chichester, UK: John Wiley & Sons.

Clarke S.E. (1998). In vitro assessment of human cytochrome P450. Xenobiotica 28, 1167–1202.

Guengerich F.P. (2000). Metabolism of chemical carcinogens. Carcinogenesis 21, 345–351.

Easterbrook J. , Lu C. , Sakai Y. , & Li A.P. (2001). Effects of organic solvents on the activities of cytochrome P450 isoforms, UDP-dependent glucuronyl transferase, and phenol sulfotransferase in human hepatocytes. Drug Metabolism and Disposition 29, 141–144.

Freyberger A. , & Scholz G. (2004). Endocrine toxicology — contributions of in vitro methods to the 3R concept. ALTEX 21, 20–27.

Anon. (2005). Guidance for Industry Safety Testing of Drug Metabolites. US Food and Drug Administration. Rockville, MD, USA: FDA. Website http://www.fda.gov/cder/guidance/6366dft.htm#_Toc101751578 (Accessed 30.09.05).

Miao Z. , Kamel A. , & Prakash C. (2005). Characterization of a novel metabolite intermediate of ziprasidone in hepatic cytosolic fractions of rat, dog, and human by esi-ms/ms, hydrogen/deuterium exchange, and chemical derivatization. Drug Metabolism and Disposition 33, 879–883.

Clark A.M. , & Hufford C.D. (1991). The use of microorganisms for the study of drug metabolism: an update. Medicinal Research Reviews 11, 473–501.

Tolonen A. , Turpeinen M. , Uusitalo J. , & Pelkonen O. (2005). A simple method for differentiation of monoisotopic drug metabolites with hydrogen-deuterium exchange liquid chromatography/electrospray mass spectrometry. European Journal of Pharmaceutical Sciences 25, 155–162.

Pelkonen O. , & Raunio H. (2005). In vitro screening of drug metabolism during drug development: Can we trust the predictions? Expert Opinion on Drug Metabolism & Toxicology 1, 49–60.

Elliott B.M. , Combes R.D. , Elcombe C. , Gatehouse D. , Gibson G.G. , & Wolf C.R. (1992). Alternatives to Aroclor 1254 for genotoxicity assays — Report of the UKEMS Working Party on Enzyme Inducers. Mutagenesis 7, 175–177.

García Franco S. , Domínguez G. , & Pico J.C. (1999). Alternatives in the induction and preparation of Phenobarbital/naphthoflavone-induced S9 and their activation profiles. Carcinogenesis 14, 323–326.

Judson P.N. , Marchant C.A. , & Vessey J.D. (2003). Using argumentation for absolute reasoning about the potential toxicity of chemicals. Journal of Chemical Information and Computer Sciences 43, 1364–1370.

Cervenková K. , Belejová M. , Veselý J. , Chmela Z. , Rypka M. , Ulrichová J. , Modrianský M. , & Maurel P. (2001). Cell suspensions, cell cultures, and tissue slices important metabolic in vitro systems. Biomedical Papers 145, 57–60.

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 detecting induction of drug metabolising enzymes: the current status. ECVAM Hepatocytes and Metabolically Competent Systems Task Force report 1. ATLA 27, 579–638.

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 Hepa RG cells. Drug Metabolism and Disposition 34, 75–83.

Glatt H. , Gemperlein I. , Setiabudi F. , Platt K.L. , & Oesch F. (1990). Expression of xenobiotic-metabolizing enzymes in propagatable cell cultures and induction of micronuclei by 13 compounds. Mutagenesis 5, 241–249.

McGregor D.B. , Edwards I. , Wolf C.R. , Forrester L.M. , & Caspari W.J. (1991). Endogenous xenobiotic enzyme levels in mammalian cells. Mutatation Research 261, 29–39.

Donato M.T. , Bassi A.M. , Gómez-Lechón M.J. , Penco S. , Herrero E. , Adamo D. , Castell J.V. , & Ferro M. (1994). Evaluation of the xenobiotic biotransformation capability of six rodent hepatoma cell lines in comparison with rat hepatocytes. In Vitro Cellular and Developmental Biology — Animal 30, 574–580.

Urani C. , Doldi M. , Crippa S. , & Camatini M. (1998). Human-derived cell lines to study xenobiotic metabolism. Chemosphere 37, 2785–2795.

Gómez-Lechón M.J. , Donato T. , Jover R. , Rodriguez C. , Ponsoda X. , Glaise D. , Castell J.V. , & Gugen-Guillouzo C. (2001). Expression and induction of a large set of drug-metabolizing enzymes by the highly differentiated human hepatoma cell line BC2. European Journal of Biochemistry 268, 1448–1459.

Gripon P. , Rumin S. , Urban S. , Le Seyecd J. , Glaise D. , Cannie I. , Guyomard C. , Lucas J. , Trepo C. , & Guguen-Guillouzo C. (2002). Infection of a human hepatoma cell line by hepatitis B virus. Proceedings of the National Academy of Sciences of the USA 99, 15655–15660.

Fabre N. , Arrivet E. , Trancard J. , Bichet N. , Roome N.O. , Prenez A. , & Vericat J-A. (2003). A new hepatoma cell line for toxicity testing at repeated doses. Cell Biology and Toxicology 19, 71–82.

Treijtel N. , Barendregt A. , Freidig A.P. , Blaauboer B.J. , & van Eijkeren J.C. (2004). Modeling the in vitro intrinsic clearance of the slowly metabolized com-pound tolbutamide determined in sandwich cultured rat hepatocytes. Drug Metabolism and Disposition 32, 884–891.

Treijtel N. , van Helvoort H. , Barendregt A. , Blaauboer B.J. , & van Eijkeren J.C.H. (2005). The use of sandwich-cultured rat hepatocytes to determine the intrinsic clearance of compounds with different extraction ratios: 7-ethoxycoumarin and warfarin. Drug Metabolism and Disposition 33, 1325–1332.

Hammond A.H. , Garle M.J. , & Fry J.R. (1999). A preliminary comparison of LiverBeads™ with a conventional rat hepatocyte culture preparation: some aspects of xenobiotic metabolism and related toxicity. ATLA 27, 111–119.

Ringel M. , von Mach M.A. , Santos R. , Feilen P.J. , Brulport M. , Hermes M. , Bauer A.W. , Schormann W. , Tanner B. , Schon M.R. , Oesch F. , & Hengstler J.G. (2005). Hepatocytes cultured in alginated microspheres: an optimized technique to study enzyme induction. Toxicology 206, 153–167.

Choi S.H. , Nishikawa M. , Sakoda A. , & Sakai Y. (2004). Feasibility of a simple double-layered coculture system incorporating metabolic processes of the intestine and live tissue: application the analysis of benzo[a]pyrene toxicity. Toxicology in Vitro 18, 393–402.

Bruinink A. , Yu D. , & Maier P. (2002). Short-term assay for the identification of neurotoxic compounds and their liver derived stable metabolites. Toxicology in Vitro 16, 717–724.

Coecke S. , Eskes C. , Gartlon J. , Vliet E.V. , Kinsner A. , Bogni A. , Raimondo L. , Parissis N. , & Langezaal I. (2002). Metabolism and neurotoxicity: the significance of genetically engineered cell lines and new three-dimensional cell cultures. ATLA 30, Suppl. 2, 115–118.

Bremer S. , Pellizzer C. , Coecke S. , Paparella M. , & Catalani P. (2002). Detection of the embryotoxic potential of cyclophosphamide by using a combined system of metabolic competent cells and embryonic stem cells. ATLA 30, 77–85.

Combes R. , Balls M. , Bansil L. , Barratt M. , Bell D. , Botham P. , Broadhead C. , Clothier R. , George E. , Fentem J. , Jackson M. , Indans I. , Laozou G. , Navaratnam V. , Pentreath V. , Phillips B. , Stemplewski H. , & Stewart J. (2002). An assessment of progress in the use of alternatives in toxicity testing since the publication of the report of the Second FRAME Toxicity Committee (1991). ATLA 30, 365–406.

Bach P.H. , Vickers A.E.M. , & Fisher R. (1996). The use of tissue slices for pharmacotoxicology studies. The report and recommendations of ECVAM workshop 20. ATLA 24, 893–923.

Martignoni M. , Monshouwer M. , de Kanter R. , Pezzetta D. , Moscone A. , & Grossi P. (2004). Phase I and phase II metabolic activities are retained in liver slices from mouse, rat, dog, monkey and human after cryopreservation. Toxicology in Vitro 18, 121–128.

Murdock G.E. , Aylott J.M. , & Westmoreland C. (1999). Comparison of hepatocyte cultures and liver slices in in vitro toxicity testing. ATLA 27, 769–781.

Catania J.M. , Parrish A.R. , Kirkpatrick D.S. , Chitkara M. , Bowden G.T. , Henderson C.J. , Wolf C.R. , Clark A.J. , Brendel K. , Fisher R.L. , & Gandolfi A.J. (2003). Precision-cut tissue slices from transgenic mice as an in vitro toxicology system. Toxicology in Vitro 17, 201–205.

Hawksworth G.M. , Bach P.H. , Nagelkerke J.F. , Dekant W. , Diezi J.E. , Harpur E. , Lock E.A. , MacDonald C. , Morin J-P. , Pfaller W. , Rutten A.A.J.J.L. , Ryan M.P. , Toutain H.J. , & Trevisan A. (1995). Nephrotoxicity testing in vitro. The report and recommendations of ECVAM workshop 10. ATLA 23, 713–727.

Gebhardt R. , Lippert C. , Schneider A. , & Doehmer J. (1999). Improved determination of drug metabolism by perifusion of recombinant V79 cells carrying human CYP3A4. Toxicology in Vitro 13, 639–643.

Pfiefer A.M.A. , Cole K.E. , Smoot D.T. , Weston A. , Groopman J.D. , Shields P.G. , Vignaud J-M. , Juillerat M. , Lipsky M.M. , Trump B. , Lechner J.F. , & Harris C.C. (1993). Simian virus 40 large tumor antigen-immortalized normal human liver epithelial cells express hepatocyte characteristics and metabolise chemical carcinogens. Proceedings of the National Academy of Sciences of the USA 90, 5123–5127.

Wiebel F.J. , Andersson T.B. , Casciano D.A. , Dickins M. , Fischer V. , Glatt H. , Horbach J. , Langenbach R.J. , Luyten W. , Turchi G. , & Vandewalle A. (1997). Genetically engineered cell lines: characterisation and applications in toxicity testing. ATLA 25, 625–639.

Doehmer J. , Krebsfänger N. , Schober W. , Luch A. , Buters J.T.M. , Jacob J. , Seidel A. , Mürdter T. , Zanger U.M. , & Eichelbaum M. (2000). Building a biotechnology platform for metabolism studies in pharmacology and toxicology. In Progress in the Reduction, Refinement and Replacement of Animal Experimentation (ed. Balls M. , van Zeller A-M. , & Halder M.E. ), pp. 139–146. Amsterdam, The Netherlands: Elsevier.

Macé K. , Offord E.A. , & Pfeifer A.M.A. (1997). Drug metabolism and carcinogen activation studies with human genetically engineered cells. In In Vitro Methods in Pharmaceutical Research (ed. Castell J.V. , & Gómez-Lechón M.J. ), pp. 433–456. London, UK: Academic Press.

Gasser R. , Funk C. , Matzinger P. , Klemisch W. , & Viger-Chougnet A. (1999). Use of transgenic cell lines in mechanistic studies of drug metabolism. Toxicology in Vitro 13, 625–632.

Crespi C. (1995). Use of genetically engineered cells for genotoxicity testing. In Environmental Mutagenesis (ed. Phillips D.H. , & Venitt S. ), pp. 233–260. Oxford, UK: Bios Scientific Publishers.

Crespi C. , & Penman B. (1997). Use of cDNA-expressed human cytochrome P450 enzymes to study potential drug–drug interactions. Advances in Pharmacology 43, 171–188.

Crespi C. , & Penman B. (1998). Use of human engineered cells in toxicology. Human and Experimental Toxicology 17, 485.

Crespi C. , Miller V. , & Penman B. (1997). Micro-titer plate assays for inhibition of human, drug-metabolising cytochromes P450. Analytical Biochemistry 248, 188–190.

Coecke S. , Catalini P. , Bull S. , Langezaal I. , Bogni A. , Bremer S. , & Balls M. (2000). The integrated use of a genetically engineered cell line panel harbouring drug metabolizing enzymes to detect metabolism related problem compounds. In Progress in the Reduction, Refinement and Replacement of Animal Experimentation (ed. Balls M. , van Zeller A-M. , & Halder M.E. ), pp. 147–157. Amsterdam, The Netherlands: Elsevier.

Yoshitomi S. , Ikemoto K. , Takahashi J. , Miki H. , Namba M. , & Asahi S. (2001). Establishment of the transformants expressing human cytochrome P450 subtypes in HepG2, and their applications on drug metabolism and toxicology. Toxicology in Vitro 15, 245–256.

Bernauer U. , Glatt H. , Heinrich-Hirsh B. , Liu Y. , Muckel E. , Vieth B. , & Gundert-Remy U. (2003). Heterologous expression of mouse cytochrome P450 2e1 in V79 cells: construction and characterisation of the cell line and comparison with V79 cell lines stably expressing rat P450 2E1 and human P450 2E1. ATLA 31, 21–30.

Bogni A. , Simi S. , Hartung T. , & Coecke S. (2006). Opportunities and limitations of using mammalian cell lines transfected with human cytochrome P450 for metabolism and toxicity studies. Critical Reviews in Toxicology (in press).

Jover R. , Bort R. , Gómez-Lechón M.J. , & Castell J.V. (1998). Re-expression of C/EBPα induces CYP26, CYP2C9 and CYP2D6 genes in HepG2 cells. FEBS Letters 431, 227–230.

Bull S. , Langezaal I. , Clothier R. , & Coecke S. (2001). A genetically engineered cell-based system for detecting metabolism-mediated toxicity. ATLA 29, 703–716.

Gülden M. , & Seibert H. (1997). Influence of protein binding and lipophilicity on the distribution of chemical compounds in in vitro systems. Toxicology in Vitro 11, 479–483.

Gómez-Lechón M.J. , Donato T. , Ponsoda X. , & Castell J.V. (2003). Human hepatic cell cultures: in vitro and in vivo drug metabolism. ATLA 31, 257–266.

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. Toxicological Sciences 73, 386–402.

Yueh M-F. , Kawahara M. , & Raucy J. (2005). Cell-based high-throughput bioassays to assess induction and inhibition of CYP1A enzymes. Toxicology in Vitro 19, 275–287.

Abourashad E.A. , Clark A.M. , & Hufford C.D. (1999). Microbial models of mammalian metabolism of xenobiotics: an updated review. Current Medicinal Chemistry 6, 359–374.

Cha C-J. , Doerge D.R. , & Cerniglia C.E. (2001). Biotransformation of malachite green by the fungus Cunninghamella elegans. Applied Environmental Microbiology 67, 4358–4360.

Parry J. (1985). A summary of the effects of benzidine, 4,4’-diaminoterphenyl, 4-dimethylaminoa-zobenzene and 4-cyanodimethylaniline as observed by the yeast group in the Second UKEMS Collaborative Study. In Comparative Genetic Toxicology — the Second UKEMS Collaborative Trial (ed. Parry J.M. , & Arlett C.F. ), pp. 267–277. Basingstoke, UK: Macmillan.

Masimirembwa C.M. , Otter C. , Berg M. , Jonsson M. , Leidvik B. , Jonsson E. , Johansson T. , Backman A. , Edlund A. , & Andersson T.B. (1999). Heterologous expression and kinetic characterization of human cytochromes P-450: validation of a pharmaceutical tool for drug metabolism research. Drug Metabolism Disposition 27, 1117–1122.

Combes R. , Barratt M. , & Balls M. (2003). An overall strategy for the testing of chemicals for human hazard and risk assessment under the EU REACH system. ATLA 31, 7–19.

Payne M.P. (2004). Computer-Based Methods for the Prediction of Chemical Metabolism and Biotrnasformation Within Biological Organisms. In Predicting Toxicity and Fate (eds Cronin M.T.D. , & Livingstone D.J. ) pp. 205–227. Boca Raton, FL, USA: CRC Press.

Soffers A.E.M.F. , Boersma M.G. , Vaes W.H.J. , Vervoort J. , Tyrakowska B. , Hermens J.L.M. , & Rietjens I.M.C.M. (2001). Computer-modeling-based QSARs for analyzing experimental data on biotransformation and toxicity. Toxicology in Vitro 15, 539–551.

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 and Clinical Pharmacology & Toxicology 96, 167–175.

Raunio H. , Taavitsainen P. , Honkakoksi P. , Juvonen R. , & Pelkonene O. (2004). In vitro methods in the prediction of kinetics of drugs: focus on drug metabolism. ATLA 32, 425–430.

De Graaf C. , Vermeulen N.P.E. , & Feenstra K.A. (2005). Cytochrome P450 in silico: an integrative modeling approach. Journal of Medicinal Chemistry 48, 2725–2755.

Vedani A. (2005). Computer-based quantification of (adverse) effects triggered by drugs and chemicals. 3R-Info-Bulletin 29, 2 pp.

Lewis D.F.V. , Lake B.G. , Bird M.G. , Loizou G.D. , Dickins M. , & Goldfarb P.S. (2003). Homology modelling of human CYP2E1 based on the CYP2C5 crystal structure: investigation of enzyme-substrate and enzyme-inhibitor interactions. Toxicology in Vitro 17, 93–105.

Lewis D.F.V. , Lake B.G. , Dickins M. , & Goldfarb P.S. (2003). Homology modelling of CYP2A6 based on the CYP2C5 crystallographic template: enzyme– substrate interactions and QSARs for binding affinity and inhibition. Toxicology in Vitro 17, 179–190.

Lewis D.F.V. , Lake B.G. , & Bird M.G. (2005). Molecular modelling of human microsomal epoxide hydrolase (EH) by homology with a fungal (Aspergillus niger) EH crystal structure of 1.8 Å resolution: structure-activity relationships in epoxides inhibiting EH activity. Toxicology in Vitro 18, 517–522.

Lewis D.F.V. (2004). Quantitative structure-activity relationships (QSARs) for substrates of human cytochromes P450 CYP2 family enzymes. Toxicology in Vitro 18, 89–97.

Dearden J.C. , Barratt M.D. , Benigni R. , Bristol D.W. , Combes R.D. , Cronin M.T.D. , Judson P.M. , Payne M.P. , Richard A.M. , Tichy M. , Worth A.P. , & Yourick J.J. (1997). The development and validation of expert systems for predicting toxicity. The report and recommendations of an ECVAM/ECB workshop (ECVAM workshop 24). ATLA 25, 223–252.

Combes R.D. , & Rodford R. (2003). The use of expert systems for toxicity prediction — illustrated with reference to the DEREK program. In Predicting Chemical Toxicity and Fate (ed. Cronin M.T.D. , & Livingstone D. ), pp. 193–204. Boca Raton, FL, USA: CRC Press.

Testa B. , Balmat A-L. , & Long A. (2004). Predicting drug metabolism: concepts and challenges. Pure and Applied Chemistry 76, 907–914.

Mekenyan O.G. , Sabchop D.D. , Pavlov T.S. , & Veith G.D. (2004). A systematic approach to simulating metabolism in computational toxicology. 1. The TIMES heuristic modelling framework. Current Pharmaceutical Design 10, 1273–1293.

Jaworska J. , Dimitrov S. , Nikolova N. , & Mekenyan O. (2002). Probabilistic assessment of biodegradability based on metabolic pathways: CATABOL System. SAR and QSAR in Environmental Research 13, 307–323.

Button W.G. , Judson P.N. , Long A. , & Vessey J.D. (2003). Using absolute and relative reasoning in the prediction of the potential metabolism of xenobiotics. Journal of Chemical Information and Computer Sciences 43, 1371–1377.

Mekenyan O. , Dimitrov S. , Schmeider P. , & Veith G. (2003). In silico modelling of hazard endpoints: current problems and perspectives. SAR and QSAR in Environmental Research 14, 361–371.

Boobis A. , Gudert-Remy U. , Kremers P. , Macheras P. , & Pelkonen O. (2002). In silico prediction of ADME and pharmacokinetics: report of an expert meeting organised by COST B 15. Journal of Pharmaceutical Sciences 17, 183–193.

Combes R.D. , & Balls M. (2005). Intelligent testing strategies for chemicals testing — a case of more haste, less speed? ATLA 33, 289–297.

Goryanin I. , Hodgman T.C. , & Selkov E. (1999). Mathematical simulation and analysis of cellular metabolism and regulation. Bioinformatics 15, 749–758.

DeJongh J. , Forsby A. , Houston J.B. , Beckman M. , Combes R. , & Blaauboer B.J. (1999). 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. Toxicology in Vitro 13, 549–554.

Blaauboer B.J. , Barratt M.D. , & Houston J.B. (1999). The integrated use of alternative methods in toxicological risk evaluation. ECVAM integrated testing stategies task force report 1. ATLA 27, 229–237.

Gubbels-van Hal W.M.L.G. , Blaauboer B.J. , Barentsen H.M. , Hoitink M.A. , Meerts I.A.T.M. , & van der Hoeven J.C.M. (2005). An alternative approach for the safety evaluation of new and existing chemicals, an exercise in integrated testing. Regulatory Toxicology and Pharmacology 42, 284–295.

Ponsoda X. , Donato M.T. , Perez-Cataldo G. , Gomez-Lechon M.J. , & Castell J.V. (2004). Drug metabolism by cultured human hepatocytes: how far are we from the in vivo reality? ATLA 32, 101–110.

Chauret N. , Gauthier A. , & Nicoll-Griffith D.A. (1998). Effect of common organic solvents on in vitro cytochrome P450-mediated metabolic activities in human liver microsomes. Drug Metabolism and Disposition 26, 1–4.

Waring J.F. , Ciurlionis R. , Jolly R.A. , Heindel M. , Gagne G. , Fagerland J.A. , & Ulrich R.G. (2003). Isolated human hepatocytes in culture display markedly different gene expression patterns depending on attachment status. Toxicology in Vitro 17, 693–701.

Combes R.D. (2004). The use of human cells in biomedical research and testing. ATLA 32, Suppl. 1, 43–49.

Serralta A. , Donato M.T. , Orbis F. , Castell J.V. , Mir J. , & Gómez-Lechón M.J. (2003). Functionality of cultured human hepatocytes from elective samples, cadaveric grafts and hepatectomies. Toxicology in Vitro 17, 769–774.

Lloyd T.D.R. , Orr S. , & Dennison A.R. (2003). A survey of consumer attitudes to the supply and use of human hepatocytes in the United Kingdom. ATLA 31, 483–488.

Bjornsson T.D. , Callaghan J.T. , Einolf H.J. , Volker F. , Gan L. , Grimm S. , Kao J. , King S.P. , Miwa G. , Ni L. , Kumar G. , McLeod J. , Obach R.S. , Roberts S. , Roe A. , Shah A. , Snikeris F. , Sullivan J.T. , Tweedie D. , Vega J.M. , Walsh J. , & Wrighton S.A. (2003). The conduct of in vitro and in vivo drug–drug interaction studies: A pharmaceutical research and manufacturers of America (PhRMA) perspective. Drug Metabolism and Disposition 31, 815–832.

Benoit J. , Cormier M. , & Wepierre J. (1987). Effect of proteins on the assessment of surfactant cytotoxicity by an in vitro test: possible correlations with in vivo data. Toxicology in Vitro 1, 91–96.

Deglmann C.J. , Ebner T. , Ludwig E. , Happich S. , Schildberg F.W. , & Koebe H.G. (2004). Protein binding capacity in vitro changes metabolism of substrates and influences the predictability of metabolic pathways in vivo. Toxicology in Vitro 18, 835–840.

Binda D. , Lasserre-Bigot D. , Bonet A. , Thomassin M. , Come M.P. , Guinchard C. , Bars R. , Jacqueson A. , & Richert L. (2003). Time course of cytochromes P450 decline during rat hepatocyte isolation and culture: effect of l-NAME. Toxicology in Vitro 17, 59–67.

Vanhaecke T. , Henkens T. , Kass G.E.N. , & Rogiers V. (2004). Effect of the histone deacetylase inhibitor trichostatin A on spontaneous apoptosis in various types of adult rat hepatocyte cultures. Biochemical Pharmacology 68, 753–760.

Richert L. , Binda D. , Hamilton G. , Viollon-Abadie C. , Alexandre E. , Bigot-Lasserre D. , Bars R. , Coassolo P. , & LeCluyse E. (2002). Evaluation of the effect of culture configuration on morphology, survival time, antioxidant status and metabolic capacities of cultured rat hepatocytes. Toxicology in Vitro 16, 89–99.

De Smet K. , Beken S. , Depreter M. , Roels F. , Vercruysse A. , & Rogiers V. (1999). Effect of epidermal growth factor in collagen gel cultures of rat hepatocytes. Toxicology in Vitro 13, 579–585.

Walker T.M. , & Woodrooffe A.J.M. (2001). Cytochrome P450 activity in control and induced long-term cultures of rat hepatocyte spheroids. Toxicology in Vitro 15, 713–719.

Papeleu P. , Vanhaecke T. , Elaut G. , Vinken M. , Henkens T. , Snykers S. , & Rogiers V. (2005). Differential effects of histone deacetylase inhibitors in tumor and normal cells — what is the toxicological relevance? Critical Reviews in Toxicology 35, 363–378.

Maurel P. , Duret C. , Gerbal-Chaloin S. , & Daujat-Chavanieu M. (2006). Differentiation of hepatocyte-like cells from human embryonic stem cells and adult liver progenitors. Proceedings of the Fifth World Congress on Alternatives and Animal Use in the Life Science, Berlin, August, 2005. ALTEX (in press).

Engl T. , Boost K.A. , Leckel K. , Beecken W-D. , Jonas D. , Oppermann E. , Auth M.K.H. , Schaudt A. , Bechstein W-O. , & Blaheta R.A. (2004). Phosphorylation of hepatocyte growth factor receptor and epidermal growth factor receptor of human hepatocytes can be maintained in a (3D) collagen gel sandwich culture system. Toxicology in Vitro 18, 527–532.

Chen H-L. , Wu H-L. , Fon C-C. , Chen P-J. , Lai MY ., & Chen D-S. (1998). Long-term culture of hepatocytes from human adults. Journal of Biomedical Sciences 5, 435–440.

Yuan J. , Liu L. , Shimada M. , Wand A. , Ruhnke M. , Heeckt P. , Muller A.R. , Nussler N.C. , Neuhaus P. , & Nussler A. (2004). Induction, expression and maintenance of cytochrome P450 isoforms in long-term cultures of primary human hepatocytes. ALTEX 21, 3–11.

Guillouzo A. (1998). Liver cell models in in vitro toxicology. Environmental Health Perspectives 106, 511–532.

Paillard F. , Finot F. , Mouche A. , Prenez A. , & Vericat J.A. (1999). Use of primary cultures of rat hepatocytes to predict toxicity in the early development of new chemical entities. Toxicology in Vitro 13, 693–700.

Combes R.D. (1989). Cytochrome P-450, mixed function oxidases and formation of genotoxic metabolites by the intestinal tract. Progress in Pharmacology 7, 119–145.

Eling T.E. , Thompson D.C. , Foureman G.L. , Curtis J.F. , & Hughes M.F. (1990). Prostaglandin synthase and xenobiotic oxidation. Annual Reviews of Pharmacology and Toxicology 30, 1–45.

Dimova S. , Brewster M.E. , Noppe M. , Jorissen M. , & Augustijns P. (2004). The use of human nasal in vitro cell systems during drug discovery and development. Toxicology in Vitro 19, 107–122.

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. ATLA 30, 151–176.

Bremer S. , & Hartung T. (2004). The use of embryonic stem cells for regulatory developmental toxicity testing in vitro — the current status of test development. Current Pharmaceutical Design 10, 2733–2747.

Hakkola J. , Pelkonen O. , Pasanen M. , & Raunio H. (1998). Xenobiotic-metabolizing cytochrome P450 enzymes in the human feto-placental unit: role in intrauterine toxicity. Critical Reviews in Toxicology 28, 35–72.

Parsons J.F. , Rockley J. , & Richold M. (1990). In vitro micromass teratogen test: interpretation of results from a blind trial of 25 compounds using three separate criteria. Toxicology in Vitro 4, 609–611.

Genschow E. , Spielmann H. , Scholz G. , Pohl I. , Seiler A. , Clemann N. , Bremer S. , & Becker K. (2004). Validation of the embryonic stem cell test in the International ECVAM validation study on three in vitro embryotoxicity tests. ATLA 32, 209–244.

Pellizzer C. , Bremer S. , & Hartung T. (2005). Developmental toxicity testing from animal towards embryonic stem cells. ALTEX 22, 47–57.

Gonzalez R.J. , & Tarloff J.B. (2004). Expression and activities of several drug-metabolizing enzymes in LLC-PK1 cells. Toxicology in Vitro 18, 887–894.

Morohoshi K. , Yamamato H. , Kamata R. , Shiraishi F. , Koda T. , & Morita M. (2005). Estrogenic activity of 37 components of commercial sunscreeen lotions evaluated by in vitro assays. Toxicology in Vitro 19, 457–469.

Combes R.D. (2000). The use of structure-activity relationships and markers of cell toxicity to detect non-genotoxic carcinogens. Toxicology in Vitro 14, 387–399.

Ekwall B. (1999). Overview of the final MEIC results: II. The in vitro–in vivo evaluation of a practical battery of cell tests for prediction of acute lethal block concentrations in humans. Toxicology in Vitro 13, 665–673.

Halle W. (2003). The registry of cytotoxicity: toxicity testing in cell cultures to predict acute toxicity (LD50) and to reduce testing in animals. ATLA 31, 89–198.

Clemedson C. , Nordin-Andersson M. , Bjerregaard H.F. , Clausen J. , Forsby A. , Gustafsson H. , Hansson U. , Isomaa B. , Jorgensen C. , Kolman A. , Kotova N. , Krause G. , Kristen U. , Kurppa K. , Romert L. , & Scheers E. (2002). Development of an in vitro test battery for the estimation of acute human systemic toxicity: An outline of the EDIT project. Evaluation-guided Development of New In Vitro Test Batteries. ATLA 30, 313–322.

MacGregor J.T. , Collins J.M. , Sugiyama Y. , Tyson C.A. , Dean J. , Smith L. , Andersen M. , Curren R.D. , Houston J.B. , Kadlubar F.F. , Kedderis G.L. , Krishnan D. , Li A.P. , Parchment R.E. , Thummel K. , Tomaszewski J.E. , Ulrich R. , Vickers A.E.M. , & Wrighton S.A. (2001). In vitro human tissue models in risk assessment: report of a consensus-building workshop. Toxicological Sciences 59, 17–36.

Combes R. , Balls M. , Curren R. , Fischbach M. , Fusenig N. , Kirkland D. , Lasne C. , Landolph J. , LeBoeuf R. , Marquardt H. , McCormick J. , Müller L. , Rivedal E. , Sabbioni E. , Tanaka N. , Vasseur P. , & Yamasaki H. (1999). Cell transformation assays as predictors of human carcinogenicity. ATLA 27, 745–767.

Mitchell I. de G. , & Combes R.D. (1997). In vitro genotoxicity and cell transformation assessment. In In vitro Methods in Pharmaceutical Research, (eds Castell J.V. , & Gómez-Lechón M.J. ), pp. 318–352. San Diego, CA, USA: Academic Press.

LeBoeuf R.A. , Kerckaert K.A. , Aardema M.J. , & Isfort R.J. (1999). Use of Syrian hamster embryo and Balb/c 3T3 cell transformation for assessing the carcinogenicity potential of chemicals. In The Use of Short- and Medium-term tests for Carcinogenic Hazard Evaluation. (ed. McGregor D.B. , Rice J.M. , & Venitt S. ) pp. 409–425. Lyon, France: IRAC Scientific Publications.

Sasaki K. , Mizusawa H. , Ishidate M. , & Tanaka N. (1990). Transformation of ras transfected BALB 3T3 clone (Bhas 42) by promoters: Application for screening and specificity of promoters. Toxicology in Vitro 4, 657–659.

Stuard S.B. , Kerckaert G.A. , & Lehman-McKeeman L.D. (1999). Characterisation of the metabolic capacity of Syrian Hamster Embryo (SHE) Cells. Toxicological Sciences 48, 366.

Coecke S. , Blaauboer B.J. , Elaut G. , Freeman S. , Freidig A. , Gensmantel N. , Hoet P. , Kapoulas V.M. , 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 A. , & van de Sandt J.J.M. (2005). Toxicokinetics and metabolism. ATLA 33, Suppl. 1, 147–175.