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Toxicological Sciences 68, 220-225 (2002)
Copyright © 2002 by the Society of Toxicology

RISK ASSESSMENT

Bacterial Lipopolysaccharide Exposure Alters Aflatoxin B1 Hepatotoxicity: Benchmark Dose Analysis for Markers of Liver Injury

James P. Luyendyk, Kate C. Shores, Patricia E. Ganey and Robert A. Roth,1

Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Institute for Environmental Toxicology, B440 Life Sciences, Michigan State University, East Lansing, Michigan 48824

ABSTRACT

Aflatoxin B1 (AFB1) is a fungal toxin that causes both acute hepatotoxicity and hepatocellular carcinoma in humans and experimental animals. Previous studies demonstrated that a small, noninjurious dose of bacterial lipopolysaccharide (LPS) augments the hepatotoxicity of AFB1 through activation of inflammatory cells and production of soluble inflammatory mediators (Barton et al., 2000b, 2001). This study was conducted to examine the effect of LPS on the dose-response relationship for AFB1-induced liver injury. Male Sprague-Dawley rats (250–350g) were treated with AFB1 (0.1 mg/kg–6.3 mg/kg, ip) and 4 h later with a noninjurious dose of E. coli LPS (7.4 x 106 EU/kg, iv). Twenty-four h after AFB1 administration, hepatic parenchymal cell injury was estimated from elevations in serum alanine aminotransferase and aspartate aminotransferase activities. Injury to intrahepatic bile ducts was evaluated from increased serum {gamma}-glutamyl transferase and alkaline phosphatase activities. Based on benchmark dose (BMD) analysis, the AFB1 BMD for parenchymal cell injury was decreased 10-fold by LPS cotreatment, whereas AFB1 BMDs for bile duct injury were decreased nearly 20-fold. The data suggest that concurrent inflammation renders the liver considerably more sensitive to the hepatotoxic effects of AFB1.

Key Words: lipopolysaccharide; aflatoxin B1; liver injury; risk assessment; benchmark dose.


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