Evaluation of Hepatic Toxicity Associated with Exposure to Hexavalent Chromium
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Background and Purpose: Use of systematic review methods to evaluate the human, animal and mechanistic evidence to effectively and transparently characterize hepatic toxicity associated with oral exposure to hexavalent chromium (CrVI).
Methods: This evaluation used a systematic review process for identifying and screening pertinent human and animal studies which examined hepatic related endpoints. A focused, stepwise analysis of the most relevant mechanistic evidence was conducted as well, prioritizing mammalian studies that focused on exposure routes more relevant to humans (e.g., oral and inhalation studies). Integration of evidence for hepatotoxicity was conducted across human, animal, and mechanistic lines of evidence.
Results: The human evidence for Cr(VI)-induced liver effects is limited by the number and confidence in the available studies. However, the available animal studies provide evidence for liver effects in rats and mice orally exposed to Cr(VI) compounds, based on histological evidence of inflammatory effects and fatty changes (i.e. lipid accumulation), as well as elevated serum enzymes suggestive of hepatotoxicity (e.g. ALT and AST). A large body of mechanistic information was identified which informs the potential hepatotoxicity of Cr(VI). A focused analysis of mechanistic evidence indicates a possible MOA of Cr(VI)-induced liver toxicity involving the production of free radicals and reactive intermediates through intracellular Cr(VI) reduction resulting in oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis. The most supported liver endpoints observed in animal models were fatty changes, chronic inflammation, and increased ALT.
Conclusions: Overall, Cr(VI) likely causes hepatic effects in humans. Cr(VI) contributes to oxidative stress in the liver, causes inflammation, increased fat storage (histologically observed as vacuolation or fatty changes), and substantial increases in serum ALT and AST, indicative of hepatocellular injury. Increased oxidative stress/pro-inflammatory status is implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and increased inflammation is associated with increased severity of nonalcoholic steatohepatitis (NASH), therefore, populations with these preexisting liver diseases (or risk factors for these diseases) represent a population of increased susceptibility to Cr(VI). The views expressed are those of the authors and do not necessarily represent the views or policies of the US EPA.