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Characterizing Adversity of Lysosomal Accumulation in Nonclinical Toxicity Studies: Results from the 5th ESTP International Expert Workshop
Citation:
Lenz, B., A. Braendli-Baiocco, J. Engelhardt, P. Fant, H. Fischer, S. Francke, R. Fukuda, S. Groeters, T. Harada, H. Harleman, W. Kaufmann, S. Kustermann, T. Nolte, X. Palazzi, G. Pohlmeyer-Esch, A. Popp, A. Romeike, A. Schulte, B. Silva Lima, L. Tomlinson, J. Willard, C. Wood, AND M. Yoshida. Characterizing Adversity of Lysosomal Accumulation in Nonclinical Toxicity Studies: Results from the 5th ESTP International Expert Workshop. TOXICOLOGIC PATHOLOGY. Society of Toxicology, RESTON, VA, 46(2):224-246, (2018).
Impact/Purpose:
There is currently a need for better alignment among toxicologic pathologists and regulatory scientists regarding how adversity is determined and characterized. This manuscript summarizes presentations and discussion at an expert workshop on adversity coordinated by the European Society of Toxicologic Pathology (ESTP). The workshop focused on accumulations within lysosomes, which have important roles in cellular metabolism. Accumulation of materials inside lysosomes represents a common finding in studies of environmental chemicals and pharmaceuticals, but one that is challenging for regulatory reviewers to consistently interpret. The primary goals of this workshop were (1) to develop a better understanding of the pathways/modes of action leading to lysosomal accumulation and potential functional consequences; (2) to provide criteria to assess adversity of histopathologic findings associated with lysosomal accumulation; and (3) to describe methods and experimental considerations to further inform adversity decisions related to lysosomal accumulation. The panel for this workshop, comprised of representatives from the European Union, Japan, and the US, shared practical case examples to illustrate issues related to assessing the adversity of different types of lysosomal accumulations. This report is the final output of the workshop. Recommendations of this workshop should increase consistency in the interpretation of adversity based on pathology findings in nonclinical studies, help integrate new types of molecular data into the review process, and facilitate a more systematic approach to communicating adversity calls in toxicology reports.
Description:
Lysosomes have a central role in cellular catabolism, trafficking, and processing of foreign particles. Accumulation of endogenous and exogenous materials in lysosomes represents a common finding in nonclinical toxicity studies. Histologically, these accumulations often lack distinctive features indicative of lysosomal or cellular dysfunction, making it difficult to consistently interpret and assign adverse dose levels. To help address this issue, the European Society of Toxicologic Pathology organized a workshop where representative types of lysosomal accumulation induced by pharmaceuticals and environmental chemicals were presented and discussed. The expert working group agreed that the diversity of lysosomal accumulations requires a case-by-case weight-of-evidence approach and outlined several factors to consider in the adversity assessment, including location and type of cell affected, lysosomal contents, severity of the accumulation, and related pathological effects as evidence of cellular or organ dysfunction. Lysosomal accumulations associated with cytotoxicity, inflammation, or fibrosis were generally considered to be adverse, while those found in isolation (without morphologic or functional consequences) were not. Workshop examples highlighted the importance of thoroughly characterizing the biological context of lysosomal effects, including mechanistic data and functional in vitro readouts if available. The information provided here should facilitate greater consistency and transparency in the interpretation of lysosomal effects.
