Characterizing Adversity of Lysosomal Accumulation in Nonclinical Toxicity Studies: Results from the 5th ESTP International Expert Workshop

Abstract

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.

Use of 3D Human Liver Organoids to Predict Drug-Induced Phospholipidosis

“…Sci. 2020, 21, 2982 2 of 18 stages [6]. PL can occur in target organs without organ-related toxicity or physiological consequences [7], however, there are cases in which PL is observed with target organ toxicity [8].…”

Safety, Pharmacokinetic, and Pharmacodynamic Evaluation of a 2′-(2-Methoxyethyl)-D-ribose Antisense Oligonucleotide–Triantenarry N-Acetyl-galactosamine Conjugate that Targets the Human Transmembrane Protease Serine 6

“…Macrophages containing granular material were observed at all dose levels in the mesenteric and axillary lymph nodes and at 6, 12, and 30 mg/kg in the mandibular lymph nodes (Supplemental Table 4). These findings were considered consistent with uptake and accumulation of the oligonucleotide at peripheral organ storage depots, and are not considered adverse (Henry et al, 2008) (Lenz et al, 2018) .…”

Cytoplasmic Vacuolation and Tapetal Changes Induced by a Novel Analgesic Agent in Beagle Dogs

“…There are no definitive criteria for determining the adversity of cytoplasmic vacuolation, particularly without any apparent functional alterations. Recently, a working group of the European Society of Toxicologic Pathology has recommended that the adversity of lysosomal accumulation should be assessed on a case-by-case basis according to following factors: (1) location and type of cell affected, (2) lysosomal content, (3) severity of the accumulation, and (4) related pathological effects as evidence of cellular or organ dysfunction (Lenz et al 2018). First, “lysosomal accumulation in tissues without regenerative capacity (e.g., neurons or retinal cells) would generally be considered adverse.” In dogs administered DMIP, morphological change in the eyes was limited to vacuolation in the tapetum lucidum, and no histopathological change was observed in neurons.…”