Title
Regulatory developmental neurotoxicity testing: A model study focussing on conventional neuropathology endpoints and other perspectives
Author
de Groot, D.M.G.
Bos-Kuijpers, M.H.M.
Kaufmann, W.S.H.
Lammers, J.H.C.M.
O'Callaghan, J.P.
Pakkenberg, B.
Pelgrim, M.T.M.
Waalkens-Berendsen, I.D.H.
Waanders, M.M.
Gundersen, H.J.J.
TNO Kwaliteit van Leven
Publication year
2005
Abstract
Our aim was to investigate a model of the morphologic approach proposed in guidelines for developmental neurotoxicity testing (DNT). Hereto, a limited DNT study [EPA Health Effects Test Guidelines OPPTS 870.6300, 1996a. Developmental Neurotoxicity Study "Public Draft", United States Environmental Protection Agency; Prevention, Pesticides and Toxic Substances (7101); EPA 712-C-96-239, June 1996. http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Drafts/870-6300.pdf was carried out with different doses of methylazoxy methanol acetate (MAM), known to affect brain morphology and neuron numbers in the developing brain. After gross examination, the brains of F1-animals were further dissected along neuro-anatomical landmarks to ensure homology between tissues of different individuals. The (relative) weight of the brain (parts) was determined. One brain half (alternating left/right to avoid lateralization) was further used for microscopic slide reading and measurement of brain layer width (linear morphometry); the other was set aside for stereologic investigation in a later phase of the study. In the offspring, a clear reduction in brain size (gross macroscopy) and weight (MAM high- and top-dose groups) was observed on postnatal days (PN) 22 and 62, but this reduction was hard to pinpoint in the microscope as the changes primarily appeared quantitative in nature, rather than qualitative. Linear measurements of brain layer width appeared very sensitive and efficient. This first step of a project is presented and the perspectives of a further stereologic investigation are discussed. © 2005 Published by Elsevier B.V.
Subject
Toxicology
Toxicology and Applied Pharmacology
Methylazoxy methanol acetate (MAM)
Microscopy and linear morphometry
Neuron numbers and stereology
Neuropathology endpoints
OECD 426)
OPPTS 870.8600, EPA
Rat
Regulatory developmental neurotoxicity (DNT) testing (Guidelines OPPTS 870.6300, EPA
methylazoxymethanol acetate
animal model
animal tissue
brain
brain development
brain size
conference paper
controlled study
developmental neurotoxicity testing
dissection
female
morphometrics
nerve cell
neuroanatomy
neuropathology
neurotoxicity
nonhuman
perinatal period
practice guideline
priority journal
qualitative analysis
rat
toxicity testing
Animalia
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http://resolver.tudelft.nl/uuid:ff0c31aa-9e00-4a14-bd82-85bf367c6855
DOI
https://doi.org/10.1016/j.etap.2004.12.039
TNO identifier
238496
ISSN
1382-6689
Source
Environmental Toxicology and Pharmacology, 19 (3), 745-755
Document type
article