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A 21st Century Update on Neurotoxicity Risk Assessment
Citation:
Boyes, W. A 21st Century Update on Neurotoxicity Risk Assessment. XIV International Congress of Toxicology, Merida, MEXICO, October 02 - 06, 2016.
Impact/Purpose:
Describes how EPA's Neurotoxicity Risk Assessment Guidelines might be reconsidered in light of more recent concepts as described in the NRC (2007) report A 21st Century Update on Neurotoxicity Risk Assessment
Description:
In 1998, EPA published Guidelines for Neurotoxicity Risk Assessment as the basis for interpreting neurotoxicity results. At that time, the focus was on traditional toxicity testing and human clinical /epidemiological data. More recently, a change in approach to toxicity testing was proposed in “A 21st Century Update on Neurotoxicity Risk Assessment “ (NRC, 2007), stating that traditional toxicity testing was too slow and expensive to develop information on the potential toxicity of the large number of untested chemicals already used in commerce. In addition, new technologies have compounded the problem as new materials, such as engineered nanomaterials, are introduced at a rate exceeding traditional testing capacity. There is currently much effort to develop higher throughput neurotoxicity testing capabilities, especially for developmental neurotoxicity, but there is no general consensus regarding how alternative testing data should be interpreted for neurotoxicity risk assessment. The dependence of critical functions, such as learning, memory or sensory perception, on the operation of integrated neural systems makes the interpretation of data from simple test assays particularly difficult. The concept of Adverse Outcome Pathways (AOP), in which molecular initiating events (MIE) trigger a sequence of steps leading to an adverse outcome, may provide a conceptual framework in which simple alternative testing data indicative of MIEs can be used to predict neurotoxic adverse effects. Neurotoxic- relevant MIEs and AOPs currently need much development. Another important concept is “fit for purpose” risk assessments: where the degree of uncertainty coincides with the decision required. An initial toxicity screen, if combined with a conservative exposure estimate, may be acceptable if there is a sufficient margin of safety between exposure and hazard. Where initial screening data are insufficient to establish a clear margin of safety, then subsequent targeted testing can be undertaken. More traditional neurotoxicity testing will be useful for those cases where margin of safety uncertainties are unresolved. Guidance is needed regarding the development of neurotoxicity relevant MIEs and AOPs, their uncertainty, and the level of evidence required for application to neurotoxicity risk assessments.This abstract does not reflect EPA policy.