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

Aflatoxin B1 (AFB1) is a fungal toxin that causes both acute hepatotoxicity and hepatocellular carcinoma in humans and ex-perimental 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 3 106 EU/kg, iv). Twenty-four h after AFB1 administration, hepatic parenchymal cell injury was esti-mated from elevations in serum alanine aminotransferase and aspartate aminotransferase activities. Injury to intrahepatic bile ducts was evaluated from increased serum g-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. Aflatoxin B1 (AFB1) is a mycotoxin produced by Aspergillus flavus and Aspergillus parisiticus. It is a common contaminant of grain foods for both human and animal consumption. Hu-man exposure to AFB1 is greatly influenced by quality of grain storage, climate, and culinary customs (Hall and Wild, 1994; Wilson and Payne, 1994). Indeed, in contrast to the United States, human exposure to AFB1 in developing countries can be quite large. Consumption of contaminated corn is probably the most important mode of exposure (Wood, 1989). In th