Toxicologist 2013 Mar; 132(1):344
Neurotoxicity in routine preclinical safety studies is traditionally assessed with three H&E-stained brain sections; an approach that is not optimal, considering the brainís complex neuroanatomy. The need to increase the sensitivity of this approach is supported by the finding that routine neuropathology assessments would fail to detect MPTP, ethanol and carbonyl sulfide induced-CNS lesions. Increasing the number of brain sections sampled and inclusion of additional histology stains have been recommended but there is no expert consensus on the feasibility of incorporating modern methods of assessment into routine preclinical safety studies. We will explore and comment on the adequacy of the traditional approach to neuropathology assessment in routine preclinical safety studies. We will also examine the current regulatory guidance on neurotoxicity assessment in routine preclinical safety studies and discuss the feasibility of changing the current approach. Examples of emerging methods, such as MRI-directed histology and detection of circulating biomarkers of CNS damage, along with strategies for incorporating these techniques into standard preclinical safety studies will also be discussed. Finally, we will attempt to build consensus on appropriate approaches for improving the sensitivity of neurotoxicity assessment in routine preclinical safety studies by fostering a discussion between the audience and panel members. This discussion will focus on the feasibility of employing the proposed new markers, endpoints, and approaches and potential issues with interpretation of results of these studies. In conclusion, we believe that by examining the adequacy of current approaches of neuropathology assessment, discussing possible improvements to regulatory guidance and presenting emerging approaches of neurotoxicity assessment that this workshop will allow for a much needed dialogue on the need and feasibility of improving the current methods of neuropathology assessment in routine preclinical safety studies.
Toxicology; Laboratory-techniques; Exposure-assessment; Central-nervous-system; Brain-function; Neurological-reactions; Clinical-diagnosis; Clinical-pathology; Clinical-techniques; Clinical-tests; Neurotoxicity; Neuropathology; Brain-electrical-activity; Histology; Safety-practices; Pyridines; Ethanols; Carbonyls; Sulfides; Biomarkers
28289-54-5; 64-17-5; 463-58-1
The Toxicologist. Society of Toxicology 52nd Annual Meeting and ToxExpo, San Antonio, Texas, March 10-14, 2013