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ToxSci Advance Access published online on August 1, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl074
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Published by Oxford University Press 2006.
Received April 28, 2006
Accepted July 28, 2006

Forum

Immunotoxicogenomics: The Potential of Genomics Technology in the Immunotoxicity Risk Assessment Process

Robert W. Luebke 1 *, Michael P. Holsapple 2, Gregory S. Ladics 3, Michael I. Luster 4, MaryJane Selgrade 1, Ralph J. Smialowicz 1, Michael R. Woolhiser 5, and Dori R. Germolec 6

1 Immunotoxicology Branch, Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, ORD, US EPA, Research Triangle Park, NC
2 International Life Sciences Institute, Health and Environmental Sciences Institute, Washington, DC
3 DuPont Crop Genetics, Wilmington, DE
4 Toxicology & Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown WV
5 Toxicology & Environmental Research & Consulting, The Dow Chemical Company, Midland, MI
6 I National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC

* To whom correspondence should be addressed.
Robert W. Luebke, E-mail: luebke.robert{at}epamail.epa.gov


  Abstract

Evaluation of xenobiotic-induced changes in gene expression as a method to identify and classify potential toxicants is being pursued by industry and regulatory agencies worldwide. A workshop was held at the Research Triangle Park campus of the Environmental Protection Agency to discuss the current state of the science of "immunotoxicogenomics", and to explore the potential role of genomics techniques for immunotoxicity testing. The genesis of the workshop was the current lack of widely accepted triggering criteria for Tier 1 immunotoxicity testing in the context of routine toxicity testing data, the realization that traditional screening methods would require an inordinate number of animals and are inadequate to handle the number of chemicals that may need to be screened (e.g., high production volume compounds) and the absence of an organized effort to address the state of the science of toxicogenomics in the identification of immunotoxic compounds. The major focus of the meeting was on the theoretical and practical utility of genomics techniques to 1) replace or supplement current immunotoxicity screening procedures, 2) provide insight into potential modes or mechanisms of action, and 3) provide data suitable for immunotoxicity hazard identification or risk assessment. The latter goal is of considerable interest to a variety of stakeholders as a means to reduce animal use and to decrease the cost of conducting and interpreting standard toxicity tests. A number of data gaps were identified that included a lack of dose response and kinetic data for known immunotoxic compounds and a general lack of data correlating genomic alterations to functional changes observed in vivo. Participants concluded that a genomics approach to screen chemicals for immunotoxic potential or to generate data useful to risk assessors holds promise, but that routine use of these methods is years in the future. However, recent progress in molecular immunology has made mode and mechanism of action studies much more practical. Furthermore, a variety of published immunotoxicity studies suggest that microarray analysis is already a practical means to explore pathway-level changes that lead to altered immune function. To help move the science of immunotoxicogenomics forward, a partnership of industry, academia and government was suggested to address data gaps, validation, quality assurance, and protocol development.


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