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)

R Mezencev; M Feshuk; L Kolaczkowski; G C Peterson; Q J Zhao; S Watford; J A Weaver

doi:10.1093/toxsci/kfae056

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)

Toxicol Sci. 2024 Apr 24:kfae056. doi: 10.1093/toxsci/kfae056. Online ahead of print.

Authors

R Mezencev¹, M Feshuk², L Kolaczkowski^{2

3}, G C Peterson¹, Q J Zhao⁴, S Watford¹, J A Weaver⁵

Affiliations

¹ Center for Public Health and Environmental Assessment, Office of Research and Development, US EPA, Washington DC.
² Center for Computational Toxicology and Exposure, Office of Research and Development, US EPA, Research Triangle Park, NC.
³ Oak Ridge Associated Universities, National Student Services Contract.
⁴ Center for Public Health and Environmental Assessment, Office of Research and Development, US EPA, Cincinnati, OH.
⁵ Center for Public Health and Environmental Assessment, Office of Research and Development, US EPA, Research Triangle Park, NC.

PMID: 38656946
DOI: 10.1093/toxsci/kfae056

Abstract

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.

Keywords: BMD; BMR; benchmark dose-response modeling; benchmark response; hepatotoxicity; liver histopathology; liver weight.

Published by Oxford University Press 2024.