In recent years, conventional toxicity testing in animals has been reinforced by in vitro methods. As a result, toxicity testing in some sectors has become more effective and at the same time more ethical. This trend is probably only at its beginning, as many of the newly-developed methods have not yet won general acceptance as a basis for the large-scale replacement and reduction of animal experimentation. What limits the wider use of these methods is validation, i.e. the evaluation of their reliability and relevance. The present paper is a short review of the validation efforts made hitherto, including projects being planned and under discussion. Our own MEIC approach is compared with other strategies. Finally, our opinion on the effectiveness of one large consensus project relative to several different smaller validation programmes is expressed — we advocate the latter strategy, because it will save time and reduce costs.
BallsN., & BridgesJ.W. (1984). The FRAME research programme on in vitro cytotoxicology. In Alternative Methods in Toxicology, Vol. 4, Acute Toxicity Testing: Alternative Approaches (ed. GoldbergA.M.), pp. 62–79. New York: Mary Ann Liebert.
2.
EkwallB. (1983). Screening of toxic compounds in mammalian cell cultures.Annals of the New York Academy of Sciences407, 64–77.
3.
FrazierJ.M. (1987). The validation approach of the Johns Hopkins Center for Alternatives to Animal Testing. In Alternative Methods in Toxicology, Vol. 5, In Vitro Toxicology: Approaches to Validation (ed. GoldbergA.M.), pp. 87–90. New York: Mary Ann Liebert.
4.
GadS.C. (1989). Acute ocular irritation evaluation: in vivo and in vitro alternatives and making them “standard” for testing. In Benchmarks: Alternative Methods in Toxicology (ed. MehlmanM.), pp. 137–193. Princeton: Princeton University Press.
5.
BallsM., BlaauboerB., BrusickD., FrazierJ., LambD., PembertonM., ReinhardtC., RoberfroidM., RosenkranzH., SchmidB., SpielmannH., StammatiA., & WalumE. (1990). Report and recommendations of the CAAT/ERGATT workshop on the validation of toxicity test procedures.ATLA18, 313–337.
6.
BondessonI., EkwallB., HellbergS., RomertL., StenbergK., & WalumE. (1989). MEIC — a new international multicentre project to evaluate the relevance to human toxicity of in vitro toxicity tests.Cell Biology and Toxicology5, 331–347.
7.
BoomanK.A., CascieriT.M., DemetruliasJ., DriedgerA., GriffithJ.F., GrochoskiG.T., KongB., McCormickW.C.3rd, North-RootH., RozenM.G., & SedlakR.I. (1988). In vitro methods for estimating eye irritancy of cleaning products. Phase I: preliminary assessment.Journal of Toxicology — Cutaneous and Ocular Toxicology7, 173–185.
8.
GettingsS.D., & McEwenG.N. (1990). Development of potential alternatives to the Draize eye test: the CTFA evaluation of alternatives program.ATLA17, 317–324.
9.
KalweitS., GernerI., & SpielmannH. (1989). Validation project of alternatives for the Draize eye test.Journal of Molecular Toxicology1, 597–603.
10.
BleinO., & AdolpheM. (1991). French project of correlation and validation of alternatives to the Draize eye irritation test.Toxicology in Vitro, in press.
11.
StammatiA., & PirovanoR. (1988). In vitro cytotoxicity test on Hep-2 cells. In Collaborative Study on Relationship Between In Vivo Primary Irritation and In Vitro Experimental Models. EEC Project 86E3-063/86-460. CEC/V/E/3/Lux/-157/99.
12.
RahmaniR., De SousaG., PlacidiM., FautrelA., ChesnéC., GuillouzoA., BrautF., PichonJ., HoellingerH., VintézouP., DiarteI., MelchionC., CordierA., LorenzonG., PenicourtM., VannierB., FournexR., PelouxA.F., BichetN., GouyD., ConoJ.P., & LounesR. (1991). A multicenter study of acute in vitro hepatic cytotoxicity.Toxicology in Vitro, in press.
13.
RosenbluthS.A., WeddingtonG.R., GuessW.L., & AutianJ. (1965). Tissue culture method for screening toxicity of plastic materials.Journal of Pharmaceutical Science54, 156–159.
14.
AutianJ. (1973). The new field of plastics toxicology: methods and results. In CRC Critical Reviews in Toxicology, Vol. 2 (ed. GolbergL.), 1–40. Cleveland: CRC Press.
15.
WilsnackR.E. (1976). Quantitative cell culture biocompatibility testing of medical devices and correlation to animal tests.Biomaterials, Medical Devices and Artificial Organs4, 235–261.
16.
EkwallB., & AcostaD. (1982). In vitro comparative toxicity of selected drugs and chemicals in HeLa cells, Chang liver cells and rat hepatocytes.Drug and Chemical Toxicology5, 219–231.
17.
EkwallB., NordenstenC., & AlbanusL. (1982). Toxicity of 29 plasticizers to HeLa cells in the MIT-24 system.Toxicology24, 199–210.
18.
WalumE., & PatersonA. (1984). On the application of cultured neuroblastoma cells in chemical toxicity screening.Journal of Toxicology and Environmental Health13, 511–520.
19.
HalleW., & GoresE. (1987). Vorhersage von LD50-werten mit der Zellkultur (Quantitiative prediction of LD50 estimations by the use of cell cultures) (German).Pharmazie42, 245–248.
20.
ClothierR.H., & HulmeL.M. (1989). Comparison of the in vitro cytotoxicities and acute in vivo toxicities of 59 chemicals.Molecular Toxicology1, 571–577.
21.
EkwallB. (1983). Correlation between cytotoxicity in vitro and LD50 values.Pharmacology and Toxicology52, Suppl. II, 80–98.
22.
FryJ.R., GarleM.J., HammondA.H., & HatfieldA. (1990). Correlation of acute lethal potency with in vitro cytotoxicity.Toxicology in Vitro4, 175–178.
23.
MehlmanM.A., PfitzerE.A., & ScalaR.A. (1989). A report on methods to reduce, refine and replace animal testing in industrial toxicology laboratories.Cell Biology and Toxicology5, 349–358.
24.
LinesmanD.A., RaczniakT.J., AaronC.S., & BaconJ.A. (1990). Comparative cytotoxicity rankings of four aminoglycoside antibodies in the Chang, SIRC and LLC-PK1 cell lines.ATLA18, 283–290.
25.
BradleyM.O., NobleC., & SinaJ.F. (1989). An in vitro nephrotoxicity assay useful in drug development.In Vitro Toxicology2, 171–182.
26.
ShopsisC., BorenfreundE., & StarkD.M. (1987). Validation studies on a battery of potential in vitro alternatives to the Draize test. In Alternative Methods in Toxicology, Vol. 5, In Vitro Toxicology: Approaches to Validation (ed. GoldbergA.M.), pp. 31–44New York: Mary Ann Liebert.
27.
Leigh tonJ., TchaoR., VerdoneJ., & NassauserJ. (1985). Macroscopic assay of focal injury in the chorio-allantoic membrane. In Alternative Methods in Toxicology, Vol. 3, A Progress Report from the Johns Hopkins Center for Alternatives to Animal Testing (ed. GoldbergA.M.), pp. 355–370. New York: Mary Ann Liebert.
28.
BagleyD.M., RizviP.Y., KongB.M., & DeSalvaS.J. (1988). An improved CAM assay for predicting ocular irritation potential. In Alternative Methods in Toxicology, Vol. 6, Progress in In Vitro Toxicology (ed. GoldbergA.M.), pp. 131–138. New York: Mary Ann Liebert.
29.
LuepkeN-P., & WallatS. (1987). HET/CAM: reproducibility studies. In Alternative Methods in Toxicology, Vol. 5, In Vitro Toxicology: Approaches to Validation (ed. GoldbergA.M.), pp. 353–363. New York: Mary Ann Liebert.
30.
RowanA.N. ed., (1989). The Alternatives Report 1, 3.North Grafton, MD: Center for Animals and Public Policy, Tufts University School of Veterinary Medicine.
31.
ReinhardtC.A., AeschbacherM., BracherM., & SpenglerJ. (1987). Validation of three cell toxicity tests and the hen's egg test with guinea-pig eye and human skin irritation data. In Alternative Methods in Toxicology, Vol. 5, In Vitro Toxicology: Approaches to Validation (ed. GoldbergA.M.), pp. 463–469. New York: Mary Ann Liebert.
32.
GordonV.C., & BergmanH.C. (1988). External validation of the EYTEX™ and EYTEX-MPA™ systems in 12 laboratories to determine the correlation of EYTEX™ results with in vivo results. In Alternative Methods in Toxicology, Vol. 6, Progress in In Vitro Toxicology (ed. GoldbergA.M.), pp. 325–331. Mew York: Mary Ann Liebert.
33.
SotoR.J., ServiM.J., & GordonV.C. (1989). Evaluation of an alternative method for ocular irritation in in vitro toxicology. In Alternative Methods in Toxicology, Vol. 7, In Vitro Toxicology: New Directions (ed. GoldbergA.M.). New York: Mary Ann Liebert.
34.
GordonV.C., KellyC.P., & BergmanH.C. (1990). Applications of the EYTEX™ method.Toxicology in Vitro4, 314–317.
35.
DierickxP.J., & GordonV.C. (1990). The EYTEX™ system and the neutral red uptake inhibition assay in cultured Hep G2 cells as alternative methods for in vivo eye irritation following the EEC protocol.ATLA17, 325–333.
36.
BallsM., RiddellR.J., HornerS.A., & ClothierR.H. (1987). The FRAME approach to the development, validation and evaluation of in vitro alternative methods. In Alternative Methods in Toxicology, Vol. 5, In Vitro Toxicology: Approaches to Validation (ed. GoldbergA.M.), pp. 45–58. New York: Mary Ann Liebert.
37.
ReaderS.J., BlackwellV., O'HaraR., ClothierR.H., GriffinG., & BallsM. (1989). A vital dye release method for assessing the short-term cytotoxic effects of chemicals and formulations.ATLA17, 28–37.
38.
MazziottiI., StammatiA., & ZuccoF. (1990). In vitro cytotoxicity of 26 coded chemicals to Hep-2 cells: a validation study.ATLA17, 401–406.
39.
BallsM., & ClothierR. (1989). Validation of alternative toxicity test systems: lessons learned and to be learned.Molecular Toxicology1, 547–559.
40.
ClothierR.H., & BallsM. (1990). Validation of alternative toxicity tests: principles, practices and cases.Toxicology in Vitro4, 692–693.
41.
BooraanK.A., DeProspoJ., DemetruliasJ., DriedgerA., GriffithJ.F., GrochoskiG., KongB., McCormickW.C.3rd, North-RootH., RozenM.G., & SedlakR.I. (1989). The SDA alternatives programme: comparison of in vitro data with Draize test data.Journal of Toxicology — Cutaneous and Ocular Toxicology8, 35–49.
42.
SpielmanH., GernerI., KalweitS., & WirnsbergerT. (1991). Validation project of alternatives to the Draize test in West Germany.Toxicology in Vitro, in press.
43.
ScalaR.A. (1987). Theoretical approaches to validation. In Alternative Methods in Toxicology, Vol. 5, In Vitro Toxicology: Approaches to Validation (ed. GoldbergA.M.), pp. 1–9. New York: Mary Ann Liebert.
44.
RundellJ.O. (1987). Validation as applied to in vitro toxicology. In Alternative Methods in Toxicology, Vol. 5, In Vitro Toxicology: Approaches to Validation (ed. GoldbergA.M.), pp. 11–15. New York: Mary Ann Liebert.
45.
FrazierJ.M., GadS.C., GoldbergA.M., & McCulleyJ.P. (1986). Validation. In Alternative Methods in Toxicology, Vol. 4, A Critical Evaluation of Alternatives to Acute Ocular Irritation Testing (ed. GoldbergA.M.), pp. 113–117. New York: Mary Ann Liebert.
46.
FrazierJ.M. (1990). Scientific Criteria for Validation of In Vitro Toxicity Tests.Paris: OECD.
47.
HellbergS., BondessonI., EkwallB., Gómez-LechónM.J., JoverR., HögbergJ., PonsodaX., RomertL., StenbergK., & WalumE. (1990). Multivariate validation of cell toxicity data: the first ten MEIC chemicals.ATLA17, 237–239.
48.
EkwallB., BondessonI., CastellJ.V., Gómez-LechónM.J., HellbergS., HögbergJ., JoverR., PonsodaX., RomertL., StenbergK., & WalumE. (1989). Cytotoxicity evaluation of the first ten MEIC chemicals: acute lethal toxicity in man predicted by cytotoxicity in five cellular assays and by oral LD50 in rodents.ATLA17, 83–100.
49.
EkwallB., Gómez-LechónM.J., HellbergS., & WalumE. (1991). Good prediction of acute toxic blood concentrations in man in 24-hour cytotoxicity to Hep-G2 and HeLa cells for the first 10 MEIC chemicals.The Toxicologist11, 227.
