In 1999 the membership of the International Life Sciences Institute (ILSI)
Health and Environmental Sciences Institute (HESI) formed a multisector consortium
to address challenges associated with the integration of genomics data into
risk assessment (Pennie et al. 2004). Following its formation, the HESI Committee
on the Application of Genomics to Mechanism-Based Risk Assessment identified
several key hurdles. These included a lack of publicly available toxicogenomics
databases, a lack of validation of available technologies, questions concerning
the comparability of different technical platforms and how transcription products
relate to toxicity, and uncertain regulatory applications.
In 2004 we have seen considerable progress in many of the areas mentioned
above, particularly in our technical ability to execute microarrays and to
analyze and interpret the resultant data. The experimental program of the HESI
Genomics Committee clearly demonstrated that it is possible to replicate data
on biologic pathways across laboratories and technical platforms (Kramer et
al. 2004; Ulrich et al. 2004). The committee's work also revealed the need
to interpret modulations in gene expression on microarrays in the context of
a broader biologic data set (e.g., clinical chemistry, histopathology). Additionally,
within the United States, the recent release of draft regulatory guidance from
the U.S. Food and Drug Administration (FDA 2003) on the use of pharmacogenomics
data in risk assessment and the release of a white paper from the U.S. Environmental
Protection Agency (U.S. EPA 2004) on potential regulatory applications of genomics
data have further focused potential applications. However, the routine application
of genomics to preclinical risk assessment has not yet been accepted universally.
Why?
The efforts of the HESI Committee on Genomics regarding experimental collaboration
and toxicogenomics database development (Mattes et al. 2004) suggest that some
of the greatest outstanding challenges relate to effective communication across
key user groups. It is critical that regulated industries share with the regulatory
community the focus of their current approaches to the use of genomics. For
example, are microarray data used primarily for early screening or for researching
mechanisms of toxicity and and under what circumstances? Additionally, open
information exchange regarding typical means of data analysis and presentation
is needed. This exchange, which has been initiated via several multisector
forums including HESI, will help ensure that a common understanding of the
technology's practical strengths and limitations is reached and allow genomics
to be applied more effectively to safety assessment. Discussions concerning
the interpretation of patterns of change in gene expression in relation to
other biologic end points will provide critical context for determining the
suitability of a data set for risk evaluation. Consensus as to when changes
in gene expression via microarray represent definitive biomarkers of effect
is also needed. Until these conditions are clarified, the utility of genomics
for classifying effects of concern will remain debatable.
The risk assessment community is also striving both to harness the collective
power of publicly available data sets and to facilitate exchange of single
data sets for safety evaluation. As such, numerous formats for the capture
and exchange of microarray and toxicology data have become available and/or
are under development (Mattes et al. 2004). Diversity of approach is not in
itself problematic and clearly has its benefits. However, the development of
flexible and comprehensible data exchange platforms that meet the needs of
multiple user groups is essential for routine exchange of toxicogenomics data.
The HESI Committee on Genomics looks forward to an ongoing role as a multi-stakeholder
consortium committed to facilitating discussion on the scientifically sound
use of genomics for risk assessment.
Syril D. Pettit
Health and Environmental Sciences Institute
International Life
Sciences Institute
Washington, DC
E-mail: spettit@ilsi.org
Syril D. Pettit is a senior scientific program manager at the ILSI Health
and Environmental Sciences Institute where she has managed collaborative
science programs since 2000.
References
FDA. 2003. Draft. Guidance for Industry. Pharmacogenomic Data Submissions.
Draft Guidance. Washington, DC:Food and Drug Administration. Available: http://www.fda.gov/cder/guidance/5900dft.pdf [accessed 26 July 2004].
Kramer JA, Pettit SD, Amin RP, Bertram TA, Car B, Cunningham M, et al.
2004. Overview of the application of transcription profiling using selected
nephrotoxicants for toxicology assessment. Environ Health Perspect 112:460-464.
Mattes WB, Pettit SD, Sansone S-A, Bushel PR, Waters MD. 2004. Database
development in toxicogenomics: issues and efforts. Environ Health Perspect
112:495-505.
Pennie W, Pettit SD, Lord PG. 2004. Toxicogenomics in risk assessment:
an overview of an HESI collaborative research program. Environ Health Perspect
112:417-419.
Ulrich RG, Rockett JC, Gibson GG, Pettit S. 2004. Overview of an interlaboratory
collaboration on evaluating the effects of model hepatotoxicants on hepatic
gene expression. Environ Health Perspect 112:423-427.
U.S. EPA. 2004. Draft. Potential Implication of Genomics for Regulatory
and Risk Assessment Applications at EPA. Washington, DC:U.S. Environmental
Protection Agency, Science Policy Council.
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Last Updated: August 6, 2004