“...the case studies applying the new methodology embodied in the Human Relevance Framework to specific tumors illustrate use of the Framework and provide instructive models for cancer risk assessors working on these tumors as well as tumors in other categories.”

This paper is highly cited because issues relating to peroxisome proliferation as it may be related to adverse human health consequences are high priorities for basic research and for risk assessment in the regulatory context. Specifically, the paper (1) provides a comprehensive state-of-the-science overview of a complex and often controversial subject, PPAR-alpha agonist-induced tumors; (2) the authorship group includes leading experts in the field; (3) with its companion paper (in the same issue of the journal), the paper introduces a "Human Relevance Framework" (HRF) that expands upon newly emerging approaches for using mode-of-action information for evaluating the human relevance of animal tumors; and (4) through the example of three case studies, the paper applies the new method to three different and specific PPAR-alpha agonist-induced tumor types.

In terms of technical information, the paper breaks ground with new information about how PPAR alpha agonists cause the pathology leading to tumors in the liver, Leydig cell, and pancreas of rodents. In addition, the case studies applying the new methodology embodied in the HRF to specific tumors illustrate use of the Framework and provide instructive models for cancer risk assessors working on these tumors as well as tumors in other categories.

A wide variety of chemicals—some herbicides, some drugs, and some natural products— cause tumors in the rodent liver and other tissues. In some cases, these tumors are associated with a marked increase in peroxisomes, an organelle normally present in the liver but at lower levels. For many years the scientific community has studied and questioned the relevance of such rodent tumors for human risk assessment—that is, whether these particular tumors are reliable predictors that comparable tumors could be expected in humans exposed to the same chemical. This paper addresses that question by reviewing the most current information (as of late 2003) on PPAR-alpha agonist-induced tumors, and by introducing and applying a "Human Relevance Framework" that promotes a systematic and transparent approach to analysis and presentation of this information.