Vulnerable processes of nervous system development: A review of markers and methods

The susceptibility of the developing nervous system to damage following exp osure to environmental contaminants has been well recognized. More recently , from a regulatory perspective, an increased emphasis has been placed on t he vulnerability of the developing nervous system to damage following pesti cide exposure. The publication of the National Academy of Sciences (NAS) re port on Pesticides in the Diets of Infants and Children (1995) and the pass age of the Food Quality Protection Act (FQPA) and Safe Drinking Water Act ( SDWA) amendments have significantly escalated the scientific debate regardi ng age-related susceptibility. Key concerns raised in the NAS report includ e the qualitative and quantitative differences that distinguish the develop ing nervous system from that of the adult. It was suggested that neurotoxic ity testing on adult animals alone may not be predictive of these differenc es in susceptibility. The age-related susceptibility of the nervous system is compounded by the protracted period of time over which this complex orga n system develops. This temporal vulnerability spans the embryonic, fetal, infant, and adolescent periods. Normal development of the nervous system re quires the concomitant and coordinated ontogeny of proliferation, migration , differentiation, synaptogenesis, gliogenesis, myelination and apoptosis t o occur in a temporally- and regionally-dependent manner. Perturbations of these processes during development can result in long-term irreversible con sequences that affect the structure and function of the nervous system and could account for qualitative differences in age-related susceptibility of the developing nervous system as compared to the adult nervous system. A di scussion of developmental milestones and the relevance of transient effects on developmental endpoints are presented. Transient effects following deve lopmental perturbations can be missed or dismissed depending on the experim ental design or screening strategy employed. This subject is discussed in l ight of scientific uncertainties regarding perturbation-induced compensatio n in the developing nervous system. Thus, utilization of age-appropriate te sts of these developmental processes may improve the detection and reduce u ncertainty about the nature of adverse effects following developmental expo sure to environmental neurotoxicants. (C) 2000 Intox Press, Inc.