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11 February 2004

Fresh Worries about Extrapolation of Rodent Toxicology Data to Humans

Study in Environmental Health Perspectives Suggests that Some Prior Research Should Be Reevaluated

[RESEARCH TRIANGLE PARK, NC] Extrapolation of animal data to humans has long been a source of controversy in the world of toxicology. New data now show that humans and rodents differ in their biological response to certain polychlorinated biphenyls (PCBs), according to a study published in the February issue of the peer-reviewed journal Environmental Health Perspectives (EHP). As a result, it may not be as simple as once assumed to extrapolate the health effects of PCBs from rodents to humans.

PCBs were banned in 1976 in the United States. However, these highly toxic chemicals are very stable over time. They are widely present in the environment and are still considered a serious health threat. Much of what is currently known about the health effects of PCBs has come from rodent studies.

Researchers already knew that binding of certain PCBs to the pregnane X receptor (PXR) in rodents produced a protective biochemical response. In this study, however, scientists examined what happens when these same PCBs bind to the human counterpart to PXR—the steroid and xenobiotic receptor (SXR). When exposed to the most stable and abundant PCBs found in human tissue, the reaction between human and rodent receptors was different.

As expected, the researchers found that several PCBs activated PXR and induced expression of target genes for metabolizing the toxicants, producing a protective biochemical reaction in rodents. However, these same PCBs antagonized the human SXR, blocking the expression of target genes and inhibiting the body’s ability to counteract harmful effects of exposure.

“ The use of rats to predict the risk of human exposure to these PCBs or mixtures that contain them will likely lead to erroneous conclusions,” the study authors write. “These findings suggest more broadly that the literature concerning the effects of xenobiotic chemicals and the attendant risks for human and wildlife populations will need to be reevaluated where the behavior of xenobiotic sensors differs across species.”

The authors further state that differences in the metabolism of drugs, xenobiotics, and dietary compounds mediated by SXR/PXR could provide both an explanation and a molecular tool with which to address the often contradictory and controversial literature on the effects of dietary and environmental chemicals on human health.

The study was a reminder of the inherent risk in extrapolating animal models to humans. “The way species react to toxicants is inherently complicated. As scientists better understand each reaction, previous assumptions are sometimes challenged,” said Dr. Jim Burkhart, science editor for EHP. “We know that PCBs are extremely toxic, but now we need to look back at some earlier research and make sure we understand what this new information means to previous findings.”

The lead author of the study was Michelle M. Tabb of the Department of Developmental and Cell Biology at the University of California, Irvine. Other authors were Vladyslav Kholodovych, Felix Grün, Changcheng Zhou, William J. Welsh, and Bruce Blumberg.

EHP is the journal of the National Institute of Environmental Health Sciences, part of the U.S. Department of Health and Human Services. More information, including the full report, is available online at http://ehponline.org/docs/2003/6560/abstract.html.

Editor’s note: Working media can register to receive press releases via e-mail by visiting www.ehponline.org/press, calling 919-541-2359, or e-mailing adams6@niehs.nih.gov.