Science Inventory

Potential Frameworks to Support Evaluation of Mechanistic Data for Developmental Neurotoxicity Outcomes: A Symposium Report

Citation:

Carlson, L., F. Champagne, D. Cory-Slechta, L. Dishaw, E. Faustman, W. Mundy, D. Segal, C. Sobin, C. Starkey, Michele Taylor, S. Makris, AND A. Kraft. Potential Frameworks to Support Evaluation of Mechanistic Data for Developmental Neurotoxicity Outcomes: A Symposium Report. NEUROTOXICOLOGY AND TERATOLOGY. Elsevier Science Ltd, New York, NY, 78:1-12, (2020). https://doi.org/10.1016/j.ntt.2020.106865

Impact/Purpose:

This manuscript summarizes the discussions of a 2016 Developmental Neurotoxicology symposium that was sponsored by NCEA on the systematic evaluation of developmental neurotoxicity mechanistic data.

Description:

Risk assessors have been charged with applying systematic review principles to epidemiological, toxicological, and mechanistic data sets. Potential uses for mechanistic data in risk assessment include providing biological plausibility, informing susceptibility, informing the human relevance of animal data, and establishing precursor events that are linked to apical outcomes. However, mechanistic data from developmental neurotoxicity (DNT) studies have been underutilized in risk assessment to date. A key challenge in systematically incorporating mechanistic data into human health assessments is that, compared to studies of apical health endpoints, these data are both more abundant (mechanistic studies routinely outnumber other studies by several orders of magnitude) and more heterogeneous (e.g. different species, test system, tissue, cell type, exposure paradigm, or specific assays performed). Mechanistic DNT evaluations are further complicated by the intricate, interconnected nature of the nervous system. A structured decision-making process for organizing, integrating, and weighing mechanistic DNT data for use in human health risk assessments will improve the consistency and efficiency of such evaluations. At the Developmental Neurotoxicology Society (DNTS) 2016 annual meeting, a symposium was held to address the application of organizing principles and frameworks for systematic evaluation of mechanistic data relevant to interpreting neurotoxicology data. Molecular events and DNT data can have positive or negative consequences, and the context of each exposure is critical, since epigenetics, tissue type, gender, stress, nutrition and other factors can modify toxicity responses in organisms. Several challenges were identified with framework development and implementation. For example, it can be difficult to determine a direction or magnitude of change in a mechanistic endpoint that can be interpreted as biologically meaningful. By examining different sources of mechanistic DNT data (in vitro experiments, epidemiologic data, molecular evidence, and epigenetics), potential organizing principles and considerations were identified that have potential to advance the use of mechanistic DNT data in risk assessments. It was also suggested that, because behavior is a manifestation of complex nervous system function, the presence and absence of behavioral change itself at different developmental stages and under different exposure conditions might be used to organize the interpretation of multiple complex simultaneous mechanistic changes.