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Characterizing "Adversity" of Pathology Findings in Nonclinical Toxicity Studies: Results from the 4th ESTP International Expert Workshop.
Citation:
Palazzi, X., J. Burkhardt, H. Caplain, V. Dellarco, P. Fant, J. Foster, S. Francke, P. Germann, S. Groeters, T. Harada, J. Harleman, K. Inui, W. Kaufmann, B. Lenz, H. Nagai, G. Pohlmeyer-Esch, A. Schulte, M. Skydsgaard, L. Tomlinson, C. Wood, AND M. Yoshida. Characterizing "Adversity" of Pathology Findings in Nonclinical Toxicity Studies: Results from the 4th ESTP International Expert Workshop. TOXICOLOGIC PATHOLOGY. Society of Toxicology, RESTON, VA, 44(6):810-824, (2016).
Impact/Purpose:
This manuscript summarizes presentations and discussion at an expert workshop coordinated by the European Society of Toxicologic Pathology (ESTP). The goal of the ESTP workshop was to review, define, and put into practical perspectives the concept of adversity for histopathological findings in nonclinical toxicity studies. These findings are the basis for many of the quantitative risk assessments conducted at EPA for environmental chemicals, air pollutants, and water contaminants. Determination of whether a particular test article effect is “adverse” or not is a critical part of the risk assessment process but one that is not well standardized across international bodies. Application of this term is also a central part of the Adverse Outcome Pathway (AOP) framework coordinated by OECD and widely supported by EPA research programs. The panel for this workshop, comprised of representatives from the European Union, Japan, and the US, shared practical case examples to illustrate issues and proposals regarding the term “adversity.” This report is the final output of the workshop. This project is meant to be a practical complement to the recommendations elaborated by the STP (US) Adversity Working Group on how to communicate adversity in nonclinical study data.
Description:
The identification of adverse health effects has a central role in the development and risk/safety assessment of chemical entities and pharmaceuticals. There is currently a need for better alignment in the toxicologic pathology community regarding how nonclinical adversity is determined and characterized. The European Society of Toxicologic Pathology (ESTP) therefore coordinated a workshop in June 2015 to review available definitions of adversity, weigh determining and qualifying factors of adversity based on case examples, and recommend a practical approach to define and characterize adversity in toxicology reports. The international group of expert pathologists and toxicologists emphasized that a holistic, weight-of-evidence, case-specific approach should be followed for each adversity assessment. It was recommended that nonclinical adversity should typically be determined at a morphological level (most often the organ) in the pathology report and should refer specifically to the test species. Final adversity calls, integration of target pharmacology/pathway information, and consideration of human translation should generally be made in toxicology overview reports. Differences in interpretation and implications of adversity calls between (agro)chemical and pharmaceutical industries and among world regions were highlighted. The results of this workshop should serve a valuable prerequisite for future organ- or lesion-specific workshops planned by the ESTP.
