The association between histopathologic effects and liver weight changes induced in mice and rats by chemical exposures: an analysis of the data from Toxicity Reference Database (ToxRefDB)

Absolute (ALW) and relative (RLW) liver weight changes are sensitive endpoints in repeat-dose rodent toxicity studies, and their changes are often used for quantitative assessment of health effects induced by hepatotoxic chemicals using the benchmark dose-response modeling (BMD) approach. To find biologically relevant liver weight changes to chemical exposures, we evaluated all data available for liver weight changes and associated liver histopathologic findings from the Toxicity Reference Database (ToxRefDB). Our analysis of 389 subchronic mouse and rat studies for 273 chemicals found significant differences in treatment-related ALW and RLW changes between dose groups with and without liver histopathologic changes. In addition, we demonstrate that chemical treatment-induced ALW and RLW changes can predict the presence of histopathologic findings and inform the selection of biologically relevant liver weight changes for BMD modeling and derivation of toxicity values.

Impact/Purpose

Organ weight changes induced by chemical exposures have been recognized as a marker of potential morphological and functional impairment; however, the strength of this association for various effect sizes and different types of histopathological changes remains to be elucidated. This project will examine comprehensively all available data for liver weight changes from the ToxRef database to determine the relationships between absolute and relative (liver-to-body) liver weight changes and the occurrence of histopathologic changes. The purpose of this study is to determine (i) which effect sizes are more likely associated with changes in histopathology, and (ii) which histopathologic changes are associated with changes in liver weight. The results will be used to inform biologically relevant BMR for liver weight changes and to support interpretation of studies with no reported or problematic results of histopathology examination.

Citation

Mezencev, R., M. Feshuk, L. Kolaczkowski, G. Peterson, Qiyu Zhao, S. Watford, AND J. Weaver. The association between histopathologic effects and liver weight changes induced in mice and rats by chemical exposures: an analysis of the data from Toxicity Reference Database (ToxRefDB). Society of Toxicology, RESTON, VA, 200(2):404-413, (2024). [DOI: 10.1093/toxsci/kfae056]

• https://academic.oup.com/toxsci/article/200/2/404/7657702

DOI: The association between histopathologic effects and liver weight changes induced in mice and rats by chemical exposures: an analysis of the data from Toxicity Reference Database (ToxRefDB)