Chemically induced proliferation of peroxisomes: implications for risk assessment

An increasing number of beneficial and economically important drugs, industrial chemicals, and agrichemicals are being found to cause a dose-related hepatomegaly in rodent species which is associated with the proliferation of the subcellular organelle, the peroxisome. The prolonged proliferation of hepatocellular peroxisomes and the enhanced production of the normal peroxisomal metabolic byproduct, hydrogen peroxide, in these animals during chronic bioassays has been hypothesized to account for the tumorigenicity of several of these compounds, most of which lack any measurable genotoxicity in in vitro and in vivo assays. This paper briefly reviews the basic morphology and enzymology of the peroxisome and its relationship to specific pathologic changes in animals. The potential impact of the mechanism of action of peroxisome proliferators upon the design of toxicity studies and, in conjunction with interspecies sensitivity data, upon risk assessment is discussed.