Data derived from in vitro toxicity studies are not directly applicable in an assessment of the toxicity of compounds in intact organisms. The major limitation is the lack of knowledge of biokinetic behaviour in vivo. Since the toxicity of a compound will be determined by the critical concentration (or other dose metric) of the critical compound (or a metabolite thereof) at the critical site of toxic action, biokinetic behaviour must be taken into account. Possibilities of biokinetic modelling on the basis of in vitro and other non-animal data are discussed, and the application of the results in hazard and risk-assessment schedules is considered.
KroesR., & FeronV.J. (1990). Toxicity testing: strategies and conduct. In Progress in Predictive Toxicology (ed. ClaysonD.B., MunroI.C., ShubikP., & SeenbergJ.A.), pp. 15–39. Amsterdam, The Netherlands: Elsevier.
2.
OECD (1993). Guidance Document for the Development of OECD Guidelines for the Testing of Chemicals. Environment Monograph No. 76, 28 pp. Paris, France: OECD.
3.
RussellW.S., & BurchR.L. (1959). The Principles of Humane Experimental Technique, 238 pp. London, UK: Methuen.
4.
EU (1986). Council Directive of 24 November 1986 on the approximation of laws, regulations and administrative provisions of the Member States regarding the protection of animals used for experimental and other purposes (Directive 86/609/EEC). Official Journal of the European CommunitiesL358, 1–29.
5.
Council of Europe (1986). European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes, ETS No. 123, 59 pp. Strasbourg, France: Council of Europe.
6.
BlaauboerB.J., BallsM., BarrattM., CasatiS., CoeckeS., MohamedM.K., MooreJ., RallD., SmithK.R., TennantR., SchwetzB.A., StokesW.S., & YounesM. (1998). 13th meeting of the Scientific Group on Methodologies for the Safety Evaluation of Chemicals (SGOMSEC): alternative testing methodologies and conceptual issues. Environmental Health Perspectives106, Suppl. 2, 413–418.
7.
BarrattM.D. (2000). Prediction of toxicity from chemical structure. Cellular and Biological Toxicology16, 1–13.
8.
EisenbrandG., Pool-ZobelB., BakerV., BallsM., BlaauboerB.J., BoobisA., CarereA., KevekordesS., LhuguenotJ-C., PietersR., & KleinerJ. (2002). Methods of in vitro toxicology. Food and Chemical Toxicology40, 193–236.
9.
NuwaysirE.F., BittnerM., TrentJ., BarrettJ.C., & AfshariC.A. (1999). Microarrays and toxicology: the advent of toxicogenomics. Molecular Carcinogenesis24, 153–159.
10.
HarriesH.M., FletcherS.T., DugganC.M., & BakerV.A. (2001). The use of genomics technology to investigate gene expression changes in cultured human liver cells. Toxicology in Vitro15, 399–405.
11.
WorthA.P., & BallsM. (2002). Alternative (non-animal) methods for chemicals testing: current status and future prospects. ATLA30, Suppl. 1, 1–125.
12.
EkwallB. (1983). Screening of toxic compounds in mammalian cell cultures. Annals of the New York Academy of Sciences407, 64–77.
13.
ForsbyA., PilliF., BianchiV., & WalumE.A. (1995). Determinations of critical cellular neurotoxic concentrations in human neuroblastoma (SH-SY5Y) cell cultures. ATLA23, 800–811.
14.
BlaauboerB.J. (2002). The applicability of in vitro-derived data in hazard identification and characterisation of chemicals. Environmental Toxicology and Pharmacology11, 213–225.
15.
AtterwillC., JohnstonH., & ThomasS.M. (1992). Models for the in vitro assessment of neurotoxicity in the nervous system in relation to xenobiotic and neurotrophic factor-mediated events. Neurotoxicology13, 39–54.
16.
FlintO.P. (1990). In vitro toxicity testing: purpose, validation and strategy. ATLA18, 11–18.
17.
FrazierJ.M. (1992). In Vitro Toxicity Testing: Applications to Safety Evaluation, 312 pp. New York, NY, USA: Marcel Dekker.
18.
BlaauboerB.J., WortelboerH.M., & MennesW.C. (1990). The use of liver cell cultures derived from different mammalian species in in vitro toxicological studies: implementation in extrapolation models?ATLA18, 251–258.
19.
RamseyJ.C., & AndersenM.E. (1984). A physiologically based description of the inhalation pharmacokinetics of styrene in rats and humans. Toxicology and Applied Pharmacology73, 159–175.
20.
ClewellH.J., & AndersenM.E. (1986). A multiple dose-route physiological model for volatile chemicals using ACSL/PC. In Languages for Continuous Simulation (ed. CellierF.E.), pp. 95. San Diego, CA, USA: Society for Computer Simulation.
21.
BrownR.P., DelpM.D., LindstedtS.L., RhombergL.R., & BelilesR.P. (1997). Physiological parameter values for physiologically based pharmacokinetic models. Toxicology and Industrial Health13, 407–484.
22.
ArturssonP., & KarlssonJ. (1991). Correlation between oral drug absorption in humans an apparent drug permeability coefficients in human intestinal epithelial (CaCo2) cells. Biochemical and Biophysical Research Communications175, 880–885.
23.
ArturssonP., & BorchardtR.T. (1997). Intestinal drug absorption and metabolism in cell cultures: Caco-2 and beyond. Pharmacological Research14, 1655–1658.
24.
KrulC., Luiten-SchuiteA., BaandaggerR., VerhagenH., MohnG., FeronV., & HavenaarR. (2000). Application of a dynamic in vitro gastrointestinal tract model to study the availability of food mutagens, using heterocyclic aromatic amines as model compounds. Food and Chemical Toxicology38, 783–792.
25.
ArturssonP., PalmK., & LuthmanK. (2001). Caco-2 monolayers in experimental and theoretical predictions of drug transport. Advanced Drug Delivery Reviews46, 27–43.
26.
MossG.P., DeardenJ.C., PatelH., & CroninM.T. (2002). Quantitative structure–permeability relationships (QSPRs) for percutaneous absorption. Toxicology in Vitro16, 299–317.
27.
CroninM.T., DeardenJ.C., GuptaR., & MossG.P. (1998). An investigation of the mechanism of flux across polydimethylsiloxane membranes by use of quantitative structure–permeability relationships. Journal of Pharmacy and Pharmacology50, 143–152.
28.
Le FerrecE., ChesneC., ArtussonP., BraydenD., FabreG., GiresP., GuillouF., RoussetM., RubasW., & ScarinoM.L. (2001). In vitro models of the intestinal barrier. The report and recommendations of ECVAM workshop 46. ATLA29, 649–668.
29.
Fiserova-BergerovaV., & DiazM.L. (1986). Determination and prediction of tissue–gas partition coefficients. International Archives of Occupational and Environmental Health58, 75–87.
30.
PoulinP., & KrishnanK. (1995). A biologically-based algorithm for predicting human tissue: blood partition coefficients of organic chemicals. Human and Experimental Toxicology14, 273–280.
31.
PoulinP., & KrishnanK. (1996). A tissue composition-based algorithm for predicting tissue: air partition coefficients of organic chemicals. Toxicology and Applied Pharmacology136, 126–130.
32.
DeJonghJ., VerhaarH.J., & HermensJ.L.M. (1997). A quantitative property–property relationship (QPPR) approach to estimate in vitro tissue–blood partition coefficients of organic chemicals in rats and humans. Archives of Toxicology72, 17–25.
33.
MeulenbergC.J., & VijverbergH.P. (2000). Empirical relations predicting human and rat tissue:air partition coefficients of volatile organic compounds. Toxicology and Applied Pharmacology165, 206–216.
34.
De KanterR., De JagerM.H., DraaismaA.L., JurvaJ.U., OlingaP., MeijerD.K., & GroothuisG.M. (2002). Drug-metabolizing activity of human and rat liver, lung, kidney and intestine slices. Xenobiotica32, 349–362.
35.
HoustonJ.B., & CarlileD.J. (1997). Prediction of hepatic clearance from microsomes, hepatocytes, and liver slices. Drug Metabolism Reviews29, 891–922.
36.
ObachR.S., BaxterJ.G., ListonT.E., SilberB.M., JonesB.C., MacIntyreF., RanceD.J., & WastallP. (1997). The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. Journal of Pharmacology and Experimental Therapeutics283, 46–58.
37.
BarrattM.D., DixitM.B., & JonesP.A. (1996). The use of in vitro cytotoxicity measurements for the prediction of the skin corrosivity potential of acids: a QSAR method. Toxicology in Vitro10, 283–290.
38.
BasketterD.A., Dooms-GoossensA., KarlbergA.T., & LepoittevinJ.P. (1995). The chemistry of contact allergy: why is a molecule allergenic?Contact Dermatitis32, 65–73.
39.
BlaauboerB.J., BarrattM.D., & HoustonJ.B. (1999). The integrated use of alternative methods in toxicological risk evaluation. ECVAM Integrated Testing Strategies Task Force Report 1. ATLA27, 229–237.
40.
AndersenM.E., ClewellH.J.3rd, GargasM.L., SmithF.A., & ReitzR.H. (1987). Physiologically based pharmacokinetics and the risk assessment process for methylene chloride. Toxicology and Applied Pharmacology87, 185–205.
41.
BlaauboerB.J., ForsbyA., HoustonJ.B., BeckmanM., CombesR. D., & DeJonghJ. (2000). An integrated approach to the prediction of systemic toxicity using biokinetic models and biological in vitro test methods. In Progress in the Reduction Refinement and Replacement of Animal Experimentation (ed. BallsM., van ZellerA-M., & HalderM.E.), pp. 525–536. Amsterdam, The Netherlands: Elsevier.
42.
ReitzR.H., MendralaA.L., ParkC.N., AndersenM.E., & GuengerichF.P. (1988). Incorporation of in vitro enzyme data into the physiologically-based pharmacokinetic (PBPK) model for methylene chloride: implications for risk assessment. Toxicology Letters43, 97–116.
43.
ClewellH.J., 3rd (1993). Coupling of computer modeling with in vitro methodologies to reduce animal usage in toxicity testing. Toxicology Letters68, 101–117.
