Evolution and current status of neurotoxicity risk assessment

The U.S. EPA neurotoxicity risk assessment guidelines define neurotoxicity as the capacity of chemical, biological, or physical agents to cause an adverse functional or structural change in the peripheral or central nervous system. Chemical-induced changes in the structure or persistent changes in behavior, neurochemistry, or neurophysiology of the nervous system are regarded as neurotoxic effects. Reversible effects occurring at doses that could endanger performance in the workplace, are associated with a known neurotoxicological mechanism of action, covary with a known neurotoxicological effect, or are latent effects uncovered by pharmacological or environmental challenge, could be considered to be neurotoxic effects. It should also be noted that even if a chemical-induced change in neurobiological function or structure does not meet the criteria established for a neurotoxic effect, the alteration could still be considered as adverse and used in a regulatory decision. Adverse effects detected by neurobiological procedures should not, however, necessarily lead to the conclusion that the chemical is a neurotoxicant. At the present time,the default RfD uncertainty factor approach is used for neurotoxicological data. A number of other safety factor approaches and quantitation dose-response models have been proposed for evaluating neurotoxicological data. However, a very limited number of comparisons have been made between the RfD approach and alternatives. In summary, neurotoxicity is one of several noncancer and points currently being used by regulatory agencies. The effective utilization of neurobiological measures to assess chemical-induced changes in the structure and function of the nervous system depends on properly designed studies and elimination of potential confounding variables that obscure interpretation of data from toxicological studies.