Toxicogenomics in risk assessment: an overview of an HESI collaborative research program.

Abstract

The value of genomic approaches in hypothesis generation is being realized as a tool for understanding toxicity and consequently contributing to an assessment of drug and chemical safety. In 1999 the membership of the International Life Sciences Institute Health and Environmental Sciences Institute formed a committee to develop a collaborative scientific program to address issues, challenges, and opportunities afforded by the emerging field of toxicogenomics. Experts and advisors from academia and government laboratories participate on the committee, along with approximately 30 corporate member organizations from the pharmaceutical, agrochemical, chemical, and consumer products industries. The committee has designed, conducted, and analyzed numerous toxicogenomic experiments within the broad fields of hepatotoxicity, nephrotoxicity, and genotoxicity. The considerable body of data generated by these programs has been instrumental in increasing understanding of sources of biological and technical variability in the alignment of toxicant-induced transcription changes with the accepted mechanism of action of these agents and the challenges in the consistent analysis and sharing of the voluminous data sets generated by these approaches. Recognizing the importance of standardized microarray data formats and public repository databases as the mechanism by which microarray data can be compared and interpreted by the scientific community, the committee has partnered with the European Bioinformatics Institute to develop a database to house the data generated by its collaborative research.

Identification of Putative Gene Based Markers of Renal Toxicity

“…This study, conducted as a consortium collaboration with the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) (Kramer et al 2004;Pennie et al 2004), compares kidney gene expression profiles induced by cisplatin and gentamicin, compounds that injure the proximal tubule, and puromycin, which produces proteinuria by selectively damaging podocytes, a key component of the glomerular filtration barrier to plasma proteins. Conventional clinical chemistry and histopathological or ultrastructural findings confirmed the induction of tubular or glomerular injury in these studies.…”

The Utility of Dna Microarrays for Characterizing Genotoxicity

“…A description of the overall objectives and design of the committee is included in this mini-monograph (Pennie et al 2004). The HESI Genotoxicity Working Group is an international collaborative effort that includes scientists from industry, academia, government, and regulatory agencies (Table 1).…”

Assessment of Biomarkers in Acetaminophen-Induced Hepatic Toxicity by siRNA

“…Profiling of gene, protein and metabolite expression has been integrated into toxicogenomics (Waters and Fostel, 2004), and this technology should help, not only in the discovery of potential biomarkers for toxicity, but also in understanding molecular and cellular mechanisms of toxicity (Pennie et al, 2004). Many scientists anticipate that toxicogenomics will prove to be a powerful tool for discovery of meaningful genes or proteins, and it may be possible to apply toxicogenomics data into regulatory decision making (Boverhof and Zacharewski, 2006) after biologic validation of toxicogenomics-based test methods (Corvi et al, 2006) and reviewing and analyzing toxicogenomics data (Leighton et al, 2006).…”