Predicting the acute liver toxicity of aflatoxin B1 in rats and humans by an in vitro-in silico testing strategy.

SCOPE: High level exposure to aflatoxin B1 (AFB1) is known to cause acute liver damage and fatality in animals and humans. The intakes actually causing this acute toxicity have so far been estimated based on AFB1 levels in contaminated foods or biomarkers in serum. The aim of the present study was to predict the doses causing acute liver toxicity of AFB1 in rat and human by an in vitro-in silico testing strategy. METHODS AND RESULTS: Physiologically based kinetic (PBK) models for AFB1 in rat and human were developed. The models were used to translate in vitro concentration-response curves for cytotoxicity in primary rat and human hepatocytes to in vivo dose-response curves using reverse dosimetry. From these data the dose levels at which toxicity would be expected were obtained and compared to toxic dose levels from available rat and human case studies on AFB1 toxicity. The results show that the in vitro-in silico testing strategy can predict dose levels causing acute toxicity of AFB1 in rats and human. CONCLUSIONS: Quantitative in vitro in vivo extrapolation (QIVIVE) using PBK modelling based reverse dosimetry can predict AFB1 doses that cause acute liver toxicity in rats and human. This article is protected by copyright. All rights reserved.