Scientific Publications by FDA Staff

Ann N Y Acad Sci 1995 Sep 15;765:198-208

Risk assessment strategies for neuroprotective agents.

Slikker W Jr, Gaylor DW

Neurotoxicity may be defined as any adverse effect on the structure or function of the central and/or peripheral nervous system by a biological, chemical, or physical agent. Neurotoxic effects may be permanent or reversible, produced by neuropharmacological or neurodegenerative properties of a neurotoxicant, or the result of direct or indirect actions on the nervous system. A multidisciplinary approach is necessary to assess neurotoxicity because of the complexity and diverse functions of the nervous system. Many of the relevant effects can be measured directly by neurochemical, neurophysiological, and neuropathological techniques, whereas, others must be inferred from observed behavior. Some neurotoxicological data can be derived directly from humans. Neurotoxicity in humans is most commonly measured by relatively noninvasive neurophysiologic and neurobehavioral methods that assess cognitive, affective, sensory, and motor function. For most toxicological assessments, however, it is necessary to rely on information derived from animal models. There are many approaches that can be used to assess neurotoxicity, including whole animal (in vivo) and tissue/cell culture (in vitro) testing. Neurotoxicity can be described at multiple levels of organization, including neurochemical, anatomical, physiological, and behavioral. An important aspect of neurotoxic endpoint evaluation involves risk assessment procedures. Risk assessment may be defined as an empirically-based process used to determine the probability that adverse or abnormal effects are associated with exposure to a chemical, physical or biological agent. Risk management, on the other hand, is the process that applies information obtained through the risk assessment process to determine whether the assessed risk should be reduced and, if so, to what extent. For chemicals such as neuroprotective agents and other drugs designed to provide therapeutic benefits, information concerning these benefits is considered during the risk management phase. The risk assessment process usually involves four steps: hazard identification, dose-response assessment, exposure assessment, and risk characterization. Neurotoxicity risk assessment models of the future may well include biomarkers of both effect and exposure as well as biologically-based mechanistic and pharmacokinetic considerations derived from both epidemiologic and experimental data.