Taking stock of toxicogenomics: mini-monograph offers overview.

Many early concerns about the utility of genomics technologies have largely been put to rest, but several issues remain to be resolved if toxicogenomics is to live up to its full potential. Chief among these is the concern that, although there is a healthy spirit of scientific collaboration and sharing within the toxicogenomics community, standardized submission of and open access to data has not yet been accomplished. The International Life Sciences Institute Health and Environmental Sciences Institute (HESI) Committee on the Application of Genomics to Mechanism-Based Risk Assessment has been actively engaged in working on these challenges by sharing experience, best operating practices, and data to achieve standardization of toxicogenomics data. In this issue, committee members William Pennie, Syril Pettit, and Peter Lord present an overview of the committee's research program [EHP 112:417-419]. The overview by Pennie and colleagues leads into the mini-monograph appearing in this issue, which explores the issues, challenges, and triumphs of using genomics in mechanism-based risk assessment.

Established in 1999, the committee is a collaborative research effort incorporating the unique perspectives and scientific talents provided by its members from government, academia, and corporate organizations representing the pharmaceutical, agrochemical, chemical, and consumer products industries. The committee has conducted and analyzed toxicogenomics experiments within the broad fields of hepatotoxicity, nephrotoxicity, and genotoxicity with two goals in mind: first, to determine whether known mechanisms of toxicity could be associated with characteristic gene expression profiles; and second, to identify technological and biological sources of variability associated with toxicogenomic experimental protocols. The answers to these questions helped the committee evaluate the usefulness of gene expression technology for the purposes of risk assessment.

There is an ongoing need for standardized submission of and open access to data. Researchers also must have access, through public repository databases, to standardized microarray data formats that are linkable to toxicology data. To address these needs, the committee has developed a database in partnership with the European Bioinformatics Institute. Based on the ArrayExpress database structure and Minimum Information About a Microarray Experiment (or MIAME) data format standards, Tox-MIAMExpress will be available to the public early in 2004, and will contain all of the data generated by the committee's research collaborations.

According to Pennie and coauthors, the committee's experimental programs have in fact shown that toxicogenomics is an inherently valuable tool for assessing toxicity. Specifically, they assert that the value of toxicogenomics is supported by the research, which has shown four things. First, patterns of gene expression relating to biological pathways are robust enough to allow insight into the mechanisms' of toxicity. Second, gene expression data can provide strong information on topographic specificity. Third, dose-dependent changes can be observed. Finally, concerns about oversensitivity of the technology may be unfounded.

The writers stress that it is important that microarray data results be considered along with other biologic end points to understand the mechanisms underlying toxicity. Pathway-level results will be much more relevant for meaningful risk assessment than single gene expression data, they write, particularly within the regulatory arena.

Clearly, toxicogenomics has come a long way in the short time since the HESI committee was first established. As the mini-monograph in this issue shows, the committee's research portfolio and collaborative approach have contributed significantly to rapid progress in the field. In all likelihood, this contribution will continue, thanks to what the authors call "this collective experience for the benefit of the regulators and regulated industries as well as for the toxicology community as a whole."

The broad impression imparted by the papers, as expressed by Pennie and colleagues in their overview of the program, is that "genomics, and more specifically toxicogenomics, can no longer be regarded as 'new' technology." With increasing experience has come increasing awareness that toxicogenomics is fast maturing. The field has proven its value with solid research and significant additions to the scientific knowledge base; its utility in mechanism-based risk assessment is less likely to be considered tentative, potential, or pending.