— There are several hundred industrial chemicals with neurotoxic potential. The neurotoxic risks of most of these chemicals are unknown. Additional methods are needed to assess the risks more effectively and to elucidate the mechanisms of neurotoxicity more accurately than is possible with the conventional methods.
This paper deals with general tasks concerning the use of in vitro models in the evaluation of neurotoxic risks. It is based on our previous studies with various in vitro models and on recent literature. The induction of glial fibrillary acidic protein in astrocyte cultures after treatment with known neurotoxicants (mercury compounds and aluminium) is discussed in more detail as an important response which can be detected in vitro.
When used appropriately with in vivo tests and with previous toxicological data, in vitro neurotoxicity testing considerably improves risk assessment. The incorporation of in vitro tests into the early stages of risk evaluation can reduce the number of animals used in routine toxicity testing, by identifying chemicals with high neurotoxic potential.
SchrierB.K. (1982). Nervous system cultures as toxicologic test systems. In Nervous System Toxicology (ed. MitchellC.L.), pp. 337–348. New York: Raven Press.
2.
AtterwillC.K. (1989). Brain reaggregate cultures in neurotoxicological investigations: studies with cholinergic neurotoxins.ATLA16, 221–230.
3.
VeronesiB. (1992). The use of cell culture for evaluating neurotoxicity. In Neurotoxicology (ed. TilsonH., MitchellC.), pp. 21–49. New York: Raven Press.
4.
KimuraH., OguraY., HashizoeM., NishiwakiH., HondaY., and IkadaY. (1994). A new vitreal drug delivery system using an implantable biodegradable polymeric device.Investigation of Ophthalmology and Visual Sciences35, 2815–2819.
5.
BruininkA., ZimmermannG., and RiesenF. (1991). Neurotoxic effects of chloroquine in vitro.Archives of Toxicology65, 480–484.
6.
Burrous O'MalleyM., and MacLeishP.R. (1993). Monoclonal antibody substrates facilitate long-term regenerative growth of adult primate retinal neurons.Journal of Neuroscience Methods47, 61–71.
7.
KhatamiM. (1988). Na+-linked active transport of ascorbate into cultured bovine retinal pigment epithelial cells: heterologous inhibition by glucose.Membrane Biochemistry7, 115–130.
8.
AtterwillC.K., BruininkA., DrejerJ., DuarteE., AbdullaE.M., MeredithC., NicoteraP., ReganC., Rodríguez-FarréE., SimpsonM.G., SmithR., VeronesiB., VijverbergH., WalumE., and WilliamsD.C. (1994). In vitro neurotoxicity testing. The report and recommendations of ECVAM workshop 3.ATLA22, 350–362, 1994.
9.
KorpelaM., & TähtiH. (1988). Human and rat erythrocyte membranes as a model for studying the effects of organic solvents on membrane-bound acetylcholinesterase in vitro.Toxicology in Vitro2, 135–139.
10.
KorpelaM., & TähtiH. (1988). The effect of in vitro and in vivo toluene exposure on the erythrocyte and synaptosome membrane integral enzymes.Pharmacology and Toxicology63, 30–32.
11.
EngelkeM., DiehlH., & TähtiH. (1992). Effects of toluene and n-hexane on rat synaptosomal membrane fluidity and integral enzyme activities.Pharmacology and Toxicology71, 343–347.
12.
FlaskosJ., McLeanW.G., and HargreavesA.J. (1994). The toxicity of organophosphate compounds towards cultured PC12 cells.Toxicology Letters70, 71–76.
13.
TähtiH., and NaskaliL. (1992). The effects of organic solvents on neural membrane integral protein tested in neural cell cultures.Neuroscience Research Communications10, 71–77.
14.
NaskaliL., OksanenH., & TähtiH. (1994). Astrocytes as targets for CNS effects of organic solvents in vitro.Neurotoxicology15, 609–612.
15.
HoneggerP., LenoirD., and FavrodP. (1979). Growth and differentiation of aggregating fetal cells in a serum-free medium.Nature282, 305–308.
16.
SkaperS.D., AdlerR., and VaronS. (1979). A procedure for purifying neuron-like cells in cultures from central nervous tissue with a defined medium.Developmental Neuroscience2, 233–237.
17.
BruininkA., MillerJ., Shah-DerlerB., SidlerC., ReiserP., BirchlerT., RasonyiT., and ZimmermanG. (1994). A serum-free neurotoxicity screening system using embryonic chick cells (SCENT).Toxicology Letters74, Suppl. 1, 10.
18.
TaniiH., HashimotoK. (1991). In vitro neurotoxicity study with dorsal root ganglia for acrylamide and its derivatves.Toxicology Letters58, 209–213.
19.
MosconaA.A. (1961). Rotation mediated histogenetic aggregation of dissociated cells: a quantifiable approach to cell interactions in vitro.Experimental Cell Research22, 455–475.
20.
PulliamL., BerensM.E., and RosenblumM.L. (1988). A normal human brain cell aggregate model for neurobiological studies.Journal of Neuroscience Research21, 521–530.
21.
EngL.F. (1988). Regulation of glial intermediate filaments in astrogliosis. In Biochemical Pathology of Astrocytes (ed. NorenbergM.D., HertzL., SchousboeA., LissA.R.), pp. 79–90. New York: Alan R. Liss.
22.
O'CallaghanJ.P., and JensenK.F. (1992). Enhanced expression of glial fibrillary acidic protein and the cupric silver degeneration reaction can be used as sensitive and early indicators of neurotoxicity.Neurotoxicology13, 113–122.
23.
O'CallaghanJ.P., and MillerD.B. (1989). Assessment of chemically induced alterations in brain development using assays of neuron- and glialocalized proteins.Neurotoxicology10, 393–406.
24.
CooksonM.R., and PentreathV.W. (1994). Alterations in the glial fibrillary acidic protein content of primary astrocyte cultures for evaluation of glial cell toxicity.Toxicology in Vitro8, 351–359.
25.
EngL.F. (1985). Glial fibrillary acidic protein (GFAP): the major protein of glial intermediate filaments in differentiated astrocytes.Journal of Neuroimmunology8, 203–214.
26.
O'CallaghanJ.P. (1991). Quantification of glial fibrillary acidic protein: comparison of slot-immunobinding assays with a novel sandwich ELISA.Neurotoxicology and Teratology13, 275–281.
27.
ToimelaT., & TähtiH. (1995). Effects of mercury, methyl mercury and aluminium on glial fibrillary acidic protein expression in rat cerebellar astrocyte cultures.Toxicology in Vitro9, 317–325.
