4 Neurotoxicity

Guidelines for testing existing neurotoxicity under the Toxic Substances chemicals for Control Act (TSCA) have been published by the U.S. Environmental Protection Agency (EPA). While the current regulatory process for assessing existing chemicals under TSCA does not use a tier-testing approach, there is widespread support for tier-testing processes. However, there is general disagreement between the Agency and the regulated community over what tests should be used for hazard identification (i. e., first-tier screening test). The regulated community sees the standard toxicity tests which are commonly conducted for systemic toxicity as sufficient for neurotoxicity screening, while the Agency regards its guideline tests as necessary to screen chemicals specifically for neurotoxicity. The guideline tests while frequently referred to as screening tests are expensive and time-consuming and therefore not widely used outside of formal existing chemicals testing programs. Development of true screening tests should be based on a mechanistic understanding of the neurobiological processes which result in neurotoxicity. The most commonly used alternative screening techniques include structure-activity analysis and in vitro methods. In vitro techniques (e.g., primary neuronal cultures, glial cell cultures, organotypic explants) are commonly used today to study mechanisms of neurotoxicity and have the potential for being used for hazard identification. Rapid, inexpensive screening tests would be expected to be useful during the early phases of new product development cycles and thus may have much more pollution prevention potential than existing methods. Such tests may eventually offer methodologies to either replace or complement tests currently used. The complex nature of the nervous system suggests that if in vitro methods gain acceptance as screening tests for neurotoxicity, they will have to be used in batteries of several assays to study multiple endpoints. ❚ DEFINING NEUROTOXICITY: CONTROVERSIAL BUT CRITICAL Neurotoxicity is one of several organ-specific endpoints used by regulatory agencies to determine hazards of chemical exposure. Definitions of neurotoxicity have been established by various organizations as the capacity of chemical, biological, or physical agents to cause adverse functional or structural changes in the central or peripheral nervous system (3, 5, 9, 10, 15, 16, 18). In each of these cases, the definition of neurotoxicity is dependent on the controversial interpretation of the word “adverse”. Tilson (12) has proposed that the definition of adverse includes alterations from a baseline state that diminishes the ability of an organism to survive, reproduce, or adapt to its environment. It has been suggested that unintended or unwanted effects should also be included under this definition (12). However, such a definition must take into account the possibility that neurobehavioral effects might be produced nonspecifically at high dose levels. Some argue that the definition of neurotoxicity should be defined more in terms of direct nervous system toxicity (5). Clarification of the definition of neurotoxicity is critical to the design of neurotoxicity screening tests, since the designer of screening tests must have a clear understanding of what the testing paradigm is expected to accomplish. For example, tests to detect blurring of vision caused by eye irritation must be designed very differently from those expected to detect vision loss due to methanol intoxication. Interpretation of the results of currently used tests for neurotoxicity can be difficult because the currently used screening tests do not necessarily distinguish between effects which are direct vs. those which are indirect. Direct effects are produced by agents or their metabolizes that produce toxicity