Principles of Screening in Toxicology with Special Emphasis on Applications to Neurotoxicology

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Abstract
It is not generally recognized that the major activity or function of classic descriptive toxicology is the use of screening tests for detecting the presence or absence of an effect, Generally, such screens have been directed at the detection of a single end point of effect, such as lethality, mutagenicity, or neurobehavioral effects. Such screens have a common set of operating characteristics that are not widely appreciated and that make traditional approaches to statistical analysis insensitive and inefficient in comparison to other available methods. Also, all too often control and historical data are not incorporated to strengthen either the design or analysis processes. Just as often overlooked is the intended objective or function of a screen, which acts as the biologic equivalent of a form of exploratory data analysis (EDA). As such, screens act to identify areas-compounds (i.e., explore or discover responses) that then either require further research (to confirm the existence of an effect and evaluate the relevance of any hazard to humans) or pass a compound on as representing low probability of a hazard. This fundamental discovery function forces screens to be designed to be very sensitive and, in so doing, requires that positive findings be understood to be flags that say “Look here” (and not that a material is, for example, a neurotoxicant). Discrimination, in other words, though important, is secondary. In this article, the characteristics and uses of screens in toxicology are presented and reviewed, along with overviews of the types and philosophy of screening operations. The relevance of these factors to the special case of neurotoxicology is pointed out, with specific examples and implications.