The susceptibility of the brain to chemicals and drugs appears to depend on its developmental stage at the time of exposure. Adverse effects on brain morphology (abnormal proliferation, differentiation and/or migration of cells) can arise, often resulting in quantitative changes, e.g. changes in neuron numbers at their final destination. Excessive neuron loss in the developing brain has negative consequences for the mental and physical abilities of the adult individual, becoming even more pronounced during senescence. However, such quantitative developmental morphological changes may go unrecognized by the morphological approach, proposed in current test guidelines for regulatory Neurotoxicity Testing, as demonstrated in the present study (American Chemistry Council, Ref.nr. 1847). A Developmental Neurotoxicity study was carried out in rats with methyl mercury chloride (MeHg) (5 dose levels). A tiered morphological approach (gross macroscopy, brain weight, slide reading, morphometry (brain layer width) was applied (EPA Guideline OPPTS 870.6300), and stereology (brain region volume, neuron number) as final step, in addition. A significant loss of cerebellar granular neurons and reduction of granular layer volume by MeHg was demonstrated using stereology. These effects, or any other effect on brain morphology, could not be depicted with previous steps in the tiered approach. The results indicate that powerful neuropathology endpoints are required to identify early effects of toxicants on developing brain morphology and suggest that stereology may provide a valuable, additional tool.
The Toxicologist. Society of Toxicology 44th Annual Meeting and ToxExpo, March 6-10, 2005, New Orleans, Louisiana