Cellular and Molecular Neurotoxicology: Basic Principles

TY - CHAP

T1 - Cellular and Molecular Neurotoxicology

T2 - Basic Principles

AU - Wallace, David R.

N1 - Funding Information: To determine whether a compound is neurotoxic, an endpoint to assess neurotoxicity must be determined and accepted. In 1998 the U.S. Environmental Protection Agency (EPA) published Guidelines for Neurotoxicity Risk Assessment, which outlined some common endpoints for the neurotoxic effects of an exogenous compound ( Table 2 ). Regarding human studies, it has been difficult to accurately determine neurotoxicity except upon postmortem examination. Recent advances in functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) imaging have improved clinical ability to determine neurological damage, but the need for relatively noninvasive and accurate biomarkers remains. Correlates between brain imaging and other secondary analyses have been attempted with manganese exposure. 4, 5 Their findings have suggested that individuals with a strong MRI signal, in conjunction with elevated manganese content in red blood cells, could be a predictor of future neurological damage associated with manganese exposure. 4 Another issue that has plagued neurotoxicology research has been the use of appropriate and comparable animal or nonanimal model systems. 6 Due to the complexity of the human CNS, it is difficult to find appropriate model systems in which modifications can be directly correlated to effects in the human CNS. Rodents are relatively inexpensive, widely used, and well characterized, but our understanding of the rodent CNS has led us to the conclusion that this may not be the best model system for all comparative studies. Some factors and issues that need to be considered when selecting an animal model are applicability to the human CNS, commonality to the human CNS, similar pathways, and neural systems compared to the human CNS. In some instances, however, rodents are used to the exclusion of other systems, even when it is understood that their use is not the best model for the system in question. 7 Alternative testing methods have been a topic of discussion for the last 2 decades. Slowly, the old dogma is evolving and there is an understanding that other species may provide as much, if not more, information compared to mammalian and vertebrate species. This effort of finding alternative testing models is supported by the federal agencies responsible for regulatory and funding matters. 8, 9 Research into other species (Drosophila, Caenorhabditis elegans, and zebra fish) has more fully elucidated the neural systems of such species, and it has become evident to the neurotoxicology community that these species can provide powerful model systems to study specific interactions of toxic agents within the CNS. These systems are significantly simpler than human, primate, or rodent CNS yet have enough complexity to examine toxic effects and neural interactions on a more focused level. The human genome project has revealed that many human genes are similar, if not exact, to our ancient ancestors. Therefore, many species previously thought of as being too “primitive” are now known to express the genes of interest in neurotoxicity testing. Ballatori and Villalobos 6 provide an excellent review of alternative species used in neurotoxicity testing.

PY - 2009/6/18

Y1 - 2009/6/18

UR - http://www.scopus.com/inward/record.url?scp=85134239361&partnerID=8YFLogxK

U2 - 10.1016/B978-032305260-3.50008-3

DO - 10.1016/B978-032305260-3.50008-3

M3 - Chapter

AN - SCOPUS:84883945811

SN - 9780323052603

SP - 7

EP - 16

BT - Clinical Neurotoxicology

PB - Elsevier

ER -