DO PEROXISOME PROLIFERATING COMPOUNDS POSE A HEPATOCARCINOGENIC HAZARD TO HUMANS

The purpose of the workshop ''Do Peroxisome Proliferating Compounds Po se a Hepatocarcinogenic Hazard to Humans?'' was to provide a review of the current state of the science on the relationship between peroxiso me proliferation and hepatocarcinogenesis. There has been much debate regarding the mechanism by which peroxisome proliferators may induce l iver tumors in rats and mice and whether these events occur in humans. A primary goal of the workshop was to determine where consensus might be reached regarding the interpretation of these data relative to the assessment of potential human risks. A core set of biochemical and ce llular events has been identified in the rodent strains that are susce ptible to the hepatocarcinogenic effects of peroxisome proliferators, including peroxisome proliferation, increases in fatty acyl-CoA oxidas e levels, microsomal fatty acid oxidation, excess production of hydrog en peroxide, increases in rates of cell proliferation, and expression and activation of the alpha subtype of the peroxisome proliferator-act ivated receptor (PPAR-alpha), Such effects have not been identified cl inically in liver biopsies from humans exposed to peroxisome prolifera tors or in in vitro studies with human hepatocytes, although PPAR-alph a is expressed at a very low level in human liver. Consensus was reach ed regarding the significant intermediary roles of cell proliferation and PPAR-alpha receptor expression and activation in tumor formation. Information considered necessary for characterizing a compound as a pe roxisome proliferating hepatocarcinogen include hepatomegaly, enhanced cell proliferation, and an increase in hepatic acyl-CoA oxidase and/o r palmitoyl-CoA oxidation levels. Given the lack of genotoxic potentia l of most peroxisome proliferating agents, and since humans appear lik ely to be refractive or insensitive to the tumorigenic response, risk assessments based on tumor data may not be appropriate. However, nontu mor data on intermediate endpoints would provide appropriate toxicolog ical endpoints to determine a point of departure such as the LED10 or NOAEL which would be the basis for a margin-of-exposure (MOE) risk ass essment approach. Pertinent factors to be considered in the MOE evalua tion would include the slope of the dose-response curve at the point o f departure, the background exposure levels, and variability in the hu man response. (C) 1998 Academic Press.